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leptin levels drop precipitously at parturition. Serum leptin concentrations are cor-
related with maternal fat mass, both during pregnancy and postpartum. Figure 3.6
graphically displays regression equations for fasting serum leptin against fat mass
during pregnancy and postpartum (Butte et al., 1997). The lines are parallel,
implying a consistent effect of fat mass on serum leptin, but the values during
pregnancy are shifted upward, suggesting that the excess leptin might be placental
in origin.
Placental weight is correlated with placental leptin mRNA (Jakimiuk et al.,
2003). Cord serum leptin was correlated with placental leptin mRNA, maternal
serum leptin, and with fetal mass (Jakimiuk et al., 2003). Large for gestational age
fetuses have higher than normal leptin, small for gestational age fetuses have
lower leptin. In twin pregnancies, the larger twin has higher circulating leptin
(Sooranna et al., 2001). In humans, cord blood leptin is associated with both
length and head circumference of neonates. Evidence supports the hypothesis that
most fetal leptin is of placental origin, though some is produced by fetal adipose
tissue. Leptin receptors are found in placenta. Human data are lacking, but in
rodents, leptin receptors are found in many if not most fetal tissues (e.g. besides
100 M. L. Power and S. D. Tardif


80

Fatsing serum leptin (ng/ml)

60



40



20



0
0 10 20 30 40 50 60
Fat mass (kg)
Pregnant 6 months postpartum

Figure 3.6 Maternal serum leptin concentrations in relation to maternal fat mass during
pregnancy and 6 months postpartum. Equations for regression lines from Butte et al.
(1997)



adopicytes also in hair follicles, cartilage, bone, lung, pancreatic islets cells, kidney,
testes, and so forth). Leptin is suspected of having endocrine, autocrine and
paracrine effects in placental and fetal tissues. It is hypothesized that leptin has
important functions in regulating fetal growth and development. But again, evi-
dence supports the hypothesis that it is permissive but may not be required. Leptin
may be a signal/marker of growth and development. Leptin is associated with
insulin, insulin-like growth factor, and growth hormone, but appears to be an
independent predictor of fetal size in humans.
Interestingly, leptin and CRH appear to have functional interactions. Recent
data suggest that CRH serves as a mediator for leptin™s anorexigenic effects. In mice
the administration of leptin decreased food intake and body weight, however, if
a CRH antagonist (alpha-helical CRH 8“41) was also administered this effect was
markedly attenuated (Masaki et al., 2003).
Leptin may play a role in the ¬ne-tuning of the timing of parturition in sheep.
Intracerebroventricular infusion of leptin into late gestation sheep fetuses inhibits
the rise in fetal circulating ACTH and cortisol (Howe et al., 2002). Whether this
effect is mediated through CRH is unknown. Energy restriction during pregnancy
in sheep and rats results in increased adipose tissue, higher circulating leptin con-
centrations, and higher food intake in the offspring (Vickers et al., 2000).
101 Maternal nutrition and metabolic control of pregnancy


GH-IGF

Growth restriction, particularly in energy-restricted pregnancies, is ultimately the
result of changes in pathways that control or are responsive to the partitioning
of oxygen and fuel molecules between the mother and the fetus. The access of
the fetus to oxygen and fuel molecules is determined by the vascular exchange
capabilities of the placenta. In a normal pregnancy, overall placental size (amount
of exchange surface) increases and the placental vasculature is reorganized, result-
ing in reduced resistance as gestation progresses (Arduini and Rizzo, 1990). In
growth-restricted human and sheep pregnancies, the normal decline in vascular
resistance is frequently impaired, re¬‚ected in higher pulsatility indices and reduced
or absent end diastolic ¬‚ow in uterine and umbilical arteries (Galan et al., 1998;
Harman and Baschat, 2003) and the placenta is frequently smaller (Heinonen
et al., 2001).
The IGF system (insulin, GH-, IGFs- and IGF-binding proteins) appears to be
a critical link in this process. The principal fetal growth factor in late gestation
appears to be IGF-1 produced by fetal liver and other tissues, whereas IGF-2 is the
principal embryonic growth factor (Gluckman and Pinal, 2003). In rats, sheep and
humans, the size of the fetus/neonate is positively correlated with maternal IGF-1
(Woodall et al., 1999; Verhaeghe et al., 2003). Increasing maternal IGF-1 in food-
restricted rat dams does not, however, increase fetal growth (Woodall et al., 1999),
suggesting that there is not a direct relation between maternal IGF-1 and placenta
function. Fetal IGF-1 is correlated with fetal size and with placental size. Hypoxia
induces increases in IGFbp-1 in the fetus, reducing availability of IGF-1, thereby
impairing growth “ through this mechanism, fetal growth is slowed under condi-
tions that re¬‚ect low substrate supply (Nayak and Giudice, 2003; Verhaeghe et al.,
2003).
Evidence from studies of human twin pregnancies (e.g. Bajoria et al., 2002)
indicate impaired amino acid transport by the placenta and a change in the IGF
axis in pregnancies complicated by IUGR. The IUGR twins had lower amino acid
concentrations, lower insulin, lower IGF-1, and higher IGFbp-1 than normal for
gestational age twins.
There is convincing evidence for placental production of growth hormones
(pGH) in sheep and primates (e.g. human and rhesus macaque). The evidence is
uncertain for placental production of growth hormones in rodents. In sheep,
secretion of growth hormone is into the fetal compartment. The existing evidence
suggests that it is unlikely there is any signi¬cant secretion into the ovine maternal
compartment. In humans, there is evidence of secretion into maternal compart-
ment, but placental growth hormone is not found in fetal blood. It is not known
for non-human primates. Humans are the only species for which data on the
102 M. L. Power and S. D. Tardif


biologic properties of placental GH exist. Placental GH has high somatogenic and
low lactogenic activity, and human pGH has a low af¬nity for lactogenic receptors
(Lacroix et al., 2002).
In humans, from 24 weeks on pituitary GH declines (and becomes effectively
non-existent) and pGH takes over its role in maternal physiology; pGH dramati-
cally declines at birth. Placental GH is not regulated by GH-releasing factors, but is
suppressed by elevated maternal glucose. The function of pGH is not completely
clear, but it likely serves to induce relative maternal insulin resistance, and encour-
ages reliance on lipolysis for maternal energy metabolism (Lacroix et al., 2002).
In sheep, pGH affects placental and fetal physiology, but pGH production is
largely restricted to early gestation (until day 50). Fetal pituitary GH expression
begins around day 50 of gestation. In humans pGH affects maternal and placental
physiology, but does not directly affect fetal physiology. However, IUGR is associ-
ated with both reduced placenta size and fewer placental cells expressing pGH, and
is associated with lower maternal pGH (Caufriez et al., 1993). In GDM, blood glu-
cose is correlated with pGH in maternal circulation. In a study comparing normal
pregnancy with pregnancies complicated by either IUGR or diabetes, maternal
serum free pGH at both 28 and 36 weeks gestation was correlated with birth weight
(Figure 3.7). Free pGH, IGF-1, and IGF-2 were all signi¬cantly lower in IUGR
pregnancies at both time periods (McIntyre et al., 2000; Figure 3.8).



100


80
Free pGH (ng/ml)




60



40


20



0
28 days 36 days
gestation gestation
IUGR Normal Macro
Figure 3.7 Free placental GH in maternal serum at gestational days 28 and 36 by growth category
(IUGR 10th percentile; macro 90th percentile)
103 Maternal nutrition and metabolic control of pregnancy


1000


800
IGF (ng/ml)




600



400



200



0
IGF-1 IGF-2
IUGR Normal
Figure 3.8 IGF-1 and IGF-2 concentrations in maternal serum at 36 days gestation


In a longitudinal study of 89 normal pregnant women, pGH was detectable as
early as 5 weeks gestation, and rose to peak values at approximately 37 weeks ges-
tation. Placental GH then decreased until parturition. Interestingly, women who
gave birth to the lightest babies had the lowest levels of pGH at term. Also, the ges-
tational age at peak pGH concentration was signi¬cantly positively correlated with
pregnancy length. In other words, an early peak of pGH was associated with an ear-
lier onset of labor, though all pregnancies were considered full term (Chellakooty
et al., 2004).



Animal models: need for diversity

Our understanding of the causes of preterm labor and IUGR remains far from
complete. Partly this is due to the dif¬culties of research in this area. Ethical con-
siderations constrain research on human beings. Experimental manipulations are
largely restricted to research on animal models. Numerous animal experiments
have documented the detrimental effects of poor maternal nutrition on pregnancy
outcome. Animal experiments have also found that maternal overnutrition and/or
obesity can adversely affect the offspring (e.g. Daenzer et al., 2002).
However, there are fundamental differences in the regulation of gestation and
parturition among mammals that complicate the use of non-human species as
models. Potential models for these conditions in humans must be carefully char-
acterized in order to evaluate the insight they can provide.
104 M. L. Power and S. D. Tardif


There is not a single path to parturition among mammals. Research on different
animal models demonstrates that evolution has produced multiple mechanisms to
achieve essentially the same end. Even within a mammalian order there are impor-
tant differences in mechanisms. For example, among rodents there are species (e.g.
rats and mice) for which the main site of steroidogenesis during pregnancy is the
corpus luteum, whereas in the guinea pig it is the placenta. Sheep (placenta) and
goats (corpus luteum) are another example of related species that differ in this fun-
damental mechanism of pregnancy. A comparison of gestation and parturition
among different mammalian species reveals intriguing differences and similarities,
but ¬nds few homologies with humans.
Sheep and rats are the most commonly used models of IUGR whereas the sheep
is by far the most commonly used animal model for the study of parturition, both
normal and preterm. Although rodent and ovine models have provided much
important information, each has signi¬cant limitations if the ultimate goal is to
apply the results to humans.
Anthropoid primates would appear to be the non-human species that are the
closest analog of human beings, and development of primate models of IUGR and
of parturition would be valuable. However, anthropoid primates have disadvan-
tages in terms of costs and potential zoonotic diseases. Their development as mod-
els for pathologies of gestation has lagged behind that of non-primate models. For
example, in a literature search in August, 2001, Schroder (2003) identi¬ed 1406
published animal experiments on fetal growth restriction. Of those experiments,
approximately 50.5% were performed on rats, and another 22.3% on mice. Other
species used included: sheep (8.7%), pig (8.3%), rabbit (5.7%), guinea pig (2.8%),
and horse (1.1%). Only 0.6% (8 out of 1406) of the identi¬ed animal experiments
were performed on non-human primates.
Recent studies suggest that the common marmoset (Callithrix jacchus), a small
(circa 350 g) New World monkey (Figure 3.9) may be a useful model in which to
examine the effects of nutritional restrictions upon gestation and later health of
infants. The common marmoset has many advantages as a non-human primate
model. Its small size and low zoonosis factor provide many advantages over other
non-human primates in terms of housing and handling, but it retains the advan-
tages of a primate over a similarly sized rodent model. Marmosets offer a particu-
larly valuable opportunity to develop useful primate models of prenatal effects on
adult disease risk, given that they have the shortest average and maximum lifespan
of any anthropoid primate.
The common marmoset has a higher rate of reproductive output than
most anthropoid primates. They are reproductively mature by 2 years of age.
Marmosets routinely produce twin fetuses, and often triplets, via multiple ovula-
tions from one or both ovaries. Triplets are more likely to be produced when
105 Maternal nutrition and metabolic control of pregnancy




Figure 3.9 The common marmoset (Callithrix jacchus)
106 M. L. Power and S. D. Tardif


females are of above average weight (Tardif and Jaquish, 1997; Tardif and Bales,
2004).
Tardif et al. (2004) have demonstrated that a modest (75% of ad lib) energy

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