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3


Maternal nutrition and metabolic control
of pregnancy
Michael L. Power1 and Suzette D. Tardif2
1
Nutrition Laboratory, Department of Conservation Biology, Smithsonian™s National Zoological Park,
Washington, DC, USA
2
Southwest National Primate Research Center, San Antonio, TX, USA




A successful human pregnancy follows a chancy path from fertilization to implan-
tation, through an extended period of placental and fetal growth, to a period of
fetal organ maturation that corresponds to a change from uterine quiescence to
coordinated uterine contractions, and ¬nally to cervical dilation and parturition.
The fate of a fertilized human ovum is far from secure (Figure 3.1). It is estimated
that one-third to one-half of human conceptuses either do not implant or are lost
shortly after implantation. Among those fertilized ova that successfully implant,
as many as one in ¬ve succumb before delivery. Even in developed nations, of




Did not implant Other congenital
defect
Early fetal loss
Preterm birth Small for
gestational age
Healthy outcome

Figure 3.1 The fate of a fertilized human ovum

88
89 Maternal nutrition and metabolic control of pregnancy


those fetuses that are delivered, 10% are preterm, 5% are small for their gestational
age, and 3% have one or more severe congenital defects (Keen et al., 2003).
A signi¬cant proportion of human morbidity and mortality, from neonates
to adults, may be attributable to events in utero. Preterm birth and intrauterine
growth restriction (IUGR) are signi¬cant sources of neonatal morbidity and mor-
tality. In 1947, Eastman (1947) declared, ˜Only when the factors underlying pre-
maturity are completely understood can any intelligent attempt at prevention be
made.™ After considerable research effort since then, our understanding of the
causes of preterm labor still is far from complete, and the rate of premature labor
and birth has not declined (Goldenberg et al., 2003). Preterm birth and IUGR are
associated; preterm delivery is more common in small for gestational age infants.
Premature and small for gestational age infants that survive into adulthood have
an increased risk of many disabilities and diseases (Ward and Beachy, 2003).
Epidemiological studies suggest relations between low birth weight and increased
risk for a variety of adult-onset diseases (Barker, 2001). There is convincing evi-
dence that events in utero can have profound effects on fetal development, and on
later expression of such traits as blood pressure, insulin/glucose metabolism, and
neural function (Seckl, 1998).
All of these adverse outcomes have causes; some are preventable, and some may
be an inherent part of the evolved human reproductive strategy that has success-
fully got us to where we are today. The challenge before us is to understand the
biology suf¬ciently to be able to predict the likely outcome of a pregnancy, and to
know whether, and how, to intervene if that predicted outcome is unwanted and
can be prevented.
Reproduction is a costly endeavor for mammalian females. Evolution likely
has favored mechanisms by which early pregnancy loss will occur if nutritional
resources available to the female are inadequate. In most anthropoid primates, the
daily energy expenditure for gestation and lactation is not great, especially when
compared with other mammals such as rodents. However, this low daily energy
expenditure is achieved partly by extending gestation and lactation over consider-
able lengths of time. Thus, each pregnancy represents a signi¬cant proportion of a
female™s reproductive life span. Early pregnancy loss and preterm birth in humans
might represent an adaptive response to circumstances that in our evolutionary
past would have led not only to fetal or neonatal demise, but would have adversely
affected the mother™s future reproduction, for example maternal death.
In this chapter we review the evidence for how inadequate or inappropriate
maternal nutrition can affect pregnancy outcome. We consider several possible
metabolic signals that might regulate these effects: corticotropin-releasing hor-
mone (CRH), leptin, and the insulin-like growth factor system. The possible role
of CRH in normal and adverse pregnancy outcomes is an important focus of this
90 M. L. Power and S. D. Tardif


chapter. Humans and other anthropoid primates are the only mammals so far
studied known to produce placental CRH (Bowman et al., 2001). In humans, ele-
vated CRH is associated with adverse pregnancy outcomes such as preterm labor
and pre-eclampsia (Goland et al., 1995). This suggests that understanding the
function and regulation of placental CRH may be a key to understanding human
gestation.



Nutrition and pregnancy outcome

The IUGR and early fetal demise are 3“10 times more prevalent in developing coun-
tries, with higher incidences of poor maternal nutrition, than they are in developed
nations (de Onis et al., 1998). In one study in rural India, 27.4% of neonates had
birth weights under 2500 g, although only 6.6% were preterm (Agarwal et al., 2002).
In a study of Australian aborigines, low body mass index (BMI 18.5 kg/m2) was
associated with ¬ve times the risk of a low birth weight baby, and 2.5 times the risk
of IUGR (Sayers and Powers, 1997). The authors concluded that 28% of low birth
weight and 15% of IUGR was attributable to maternal malnutrition. Filipino women
with low energy status (as determined by maternal arm fat area) gave birth to male
offspring that, 15 years later, had higher total cholesterol and a higher low density
lipoprotein (LDL) to high density lipoprotein (HDL) cholesterol ratio than did
women in better condition. The ¬ndings in the female offspring were less consistent,
suggesting a possible sex difference in the relation between fetal nutrition and post-
natal lipid metabolism (Kuzawa and Adair, 2003).
Two hypotheses have been proposed to explain the link between low birth
weight and later vulnerability to disease: poor fetal nutrition (Barker, 2001) and
fetal exposure to excess glucocorticoids (Seckl, 1998). Poor maternal nutrition can
contribute towards either mechanism. For example, maternal undernutrition,
especially protein-energy malnutrition, appears to down regulate the placental
enzyme 11 -hydroxysteroid dehydrogenase type 2, which acts as a barrier to glu-
cocorticoids (Seckl, 1998). This has been shown de¬nitively in the rat (Bertram
et al., 2001; Lesage et al., 2001). Thus, maternal malnutrition potentially exposes
the fetus to increased maternal glucocorticoids. Seckl and colleagues provide a
detailed examination of the evidence for glucocorticoid programming of physiol-
ogy, and its links to disease in their contribution to this volume.
In contrast to poor women in developing nations, pregnant women in devel-
oped nations (and the more ˜well-off ™ segments of the populations in developing
nations) are at higher risk of obesity, and its attendant sequelea of metabolic dis-
orders such as gestational diabetes mellitus (GDM). These disorders of ˜plenty™ also
can result in poor fetal outcomes, such as fetal macrosomia, and are associated
91 Maternal nutrition and metabolic control of pregnancy


with a propensity to obesity and type 2 diabetes in later life for the offspring. In
a study of pregnant Danish women (Jensen et al., 2003), both overweight and
obese women were signi¬cantly more at risk for having a large for gestational age
infant, in addition to hypertensive disorders during pregnancy, and requiring the
induction of labor or Cesarian section. In a study of Australian women, women
with non-insulin dependent diabetes during pregnancy were signi¬cantly heavier
and had greater BMIs than women with uncomplicated pregnancies. In contrast,
women in this study with IUGR pregnancies were signi¬cantly lighter (McIntyre
et al., 2000). Thus, current evidence supports the idea that the risk of an adverse
pregnancy outcome is related to BMI by a U-shaped curve.
In addition to maternal energy intake, micronutrient de¬ciencies (or excess) can
adversely affect pregnancy outcome. A prime example is folate de¬ciency, which
is associated with neural tube defects. An early intervention study by Ebbs and col-
leagues (1941) found that women with a poor diet (de¬ned as low in protein, cal-
cium, and fruits and vegetables) had higher incidences of miscarriages, stillbirths
and early neonatal mortality. Inadequate maternal intake of the vitamins B-6,
B-12, K, and folate, and the minerals copper, magnesium and zinc, have been asso-
ciated with abnormal prenatal development, as have excessive maternal intake of
vitamins A and D, and of the minerals iodine and iron (Keen et al., 2003). Low
maternal intake of vitamin C has been linked with premature rupture of mem-
branes (Siega-Riz et al., 2003).
Micronutrient de¬ciencies can arise because of poor maternal diet, or secondar-
ily due to genetic factors, nutrient interactions, drug interactions, or alterations of
metabolism due to disease. For example, people with Menkes disease suffer from
copper de¬ciency due to genetically based defects in the intracellular transport of
copper (Keen et al., 1998). People with phytate-rich diets are susceptible to zinc
de¬ciency due to the mineral-binding capacity of phytate (Hambidge, 2000).
Diabetes and hypertension alter the metabolism of zinc, copper and other miner-
als (Keen et al., 1998).
There are many known risk factors for preterm birth, including previous preterm
birth, uterine infection, IUGR and maternal psychosocial stress. Inappropriate mater-
nal nutrition might increase the risk of preterm birth in a number of ways. For
example, protein-energy malnutrition and malnutrition in a number of micro-
nutrients (e.g. zinc, vitamins C and E) are known to adversely affect immune status
(Goldenberg, 2003). A compromised immune system increases the risk of uterine
infection, which in turn is associated with an increased risk of preterm birth.
This is a plausible scenario. Infections, parasitic diseases, malnutrition and poor
pregnancy outcomes are often associated (Romero et al., 2003; Steketee, 2003).
However, evidence is lacking that mineral and vitamin supplementation can improve
pregnancy outcomes by reducing infections (Goldenberg, 2003). An overview of
92 M. L. Power and S. D. Tardif


randomized controlled trials could not identify any speci¬c nutrient that was asso-
ciated with reducing preterm birth (Villar et al., 2003).
Numerous endocrine and exocrine pathways may be involved in the relations
among nutritional state and pregnancy outcome. We highlight three potential
pathway systems: the CRH-cortisol, leptin and growth hormone insulin-like
growth factor (GH-IGF).



CRH-cortisol

Activation of the fetal hypothalamic“pituitary“adrenal (HPA) axis is a common
¬nding at the end of pregnancy in many mammals. It results in increased output
of fetal glucocorticoids that contribute to mechanisms that mature fetal organs
necessary for life after birth. Steroid production from the fetal adrenal is also
important in pathways leading to the ending of uterine quiescence, and the initia-
tion of labor and parturition.
The primate has a unique fetal adrenal in function, morphology and maturation
(Jaffe et al., 1998). It is characterized by rapid growth, such that it is dispropor-
tionately enlarged in late gestation, and high steroidogenic activity. The majority of
the primate fetal adrenal consists of a fetal zone that atrophies soon after birth, and
has no counterpart postpartum. The primate adrenal fetal zone produces large
quantities of dehydroepiandrosterone sulphate (DHEA-S); up to 200 mg/day dur-
ing late gestation. DHEA-S is converted to estrogen in the placenta, a vital step in
the initiation of the cascade of physiologic events leading to labor. The fetal adre-
nal produces cortisol in the transitional zone, which is essential for the mainte-
nance of intrauterine homeostasis and induction of enzymes in a variety of organs
in preparation for extrauterine existence (Jaffe et al., 1998). The transitional zone
production of glucocorticoids increases rapidly at mid-pregnancy and levels remain
elevated throughout the remainder of normal pregnancies (Smith et al., 1999;
Umezaki et al., 2001). This pro¬le is typical of primates and has been reported for
common marmosets (Ziegler and Sousa, 2002), rhesus monkeys (Umezaki et al.,
2001), baboons (Pepe et al., 1990), gorillas and chimpanzees (Smith et al., 1999)
and humans (Jaffe et al., 1998; Goland et al., 1994).
The CRH is a neuropeptide produced in the brain in hypothalamic regions such
as the paraventricular nucleus (PVN), and in extra hypothalamic sites such as the
amygdala and the bed nucleus of the stria terminalis. The CRH stimulates adreno-
corticotropin-releasing hormone (ACTH) production by the pituitary gland,
which in turn stimulates cortisol production in the adrenal glands. Cortisol
restrains CRH production by the hypothalamus via a negative feedback mecha-
nism. However, cortisol stimulates CRH production in extra hypothalamic sites in
93 Maternal nutrition and metabolic control of pregnancy


300

Immunoreactive CRH (% of baseline)
0.05
P
250

0.05
P
200


150


100


50


0
Baseline Pre-prandial Prandial Post-prandial
Figure 3.2 CRH response to feeding in central nucleus of the rat amygdala. Mean baseline de¬ned
as 100%. Pre-prandial is 30 min prior to feeding; post-prandial is 30 min after feeding.
Data obtained using microdialysis. Adapted from Merali et al. (1998) with permission




a feed-forward mechanism that helps sustain central motive states. Detailed informa-
tion on neural regulation of CRH is reviewed in the chapter by Watts in this volume.
The upregulation of CRH by glucocorticoids in extrahypothalamic regions of
the brain is linked to conditions of adversity or stress. It can result in fearful and
anxious behaviors (see contribution by Schulkin and colleagues in this volume).
However, upregulation of CRH in the amygdala is also seen in appetitive events
such as feeding (Merali et al., 1998; Figure 3.2). Some (e.g. Merali et al., 2003) have
suggested that the CRH system serves to increase alertness and attention to cues of
biological signi¬cance. Cues that represent a threat to survival elicit fear; cues that
represent aid to survival (e.g. food intake) elicit approach and appetitive behaviors;
both types of cue increase CRH in the central nucleus of the amygdala.
Interestingly, sucrose ingestion can down-regulate CRH in the PVN. Sucrose
ingestion (and perhaps most feeding?) apparently results in a transient increase in
serum cortisol, which then exerts a suppresive effect on hypothalamic CRH. Dallman
and colleagues have proposed this as a mechanism to understand ˜comfort foods™
(Dallman et al., 2003). However, evidence suggests that sucrose ingestion may have
direct effects on CRH expression. Adrenalectomized rats given saccharin to drink
have higher CRH and lower serum insulin than sham adrenalectomized controls.

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