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The placenta is the center of the chronic disease universe

Kent L. Thornburg, PhD; Nicole Marshall, MD

O ver the past quarter century, the scientific community

has gained a new perspective on the origins of chronic
disease, which now includes a central role for the placenta. It
in one generation if babies were born at the lowest risk
birthweight and did not cross body mass index (BMI) centiles
in childhood.
began when the team of Barker et al1 reported an inverse Much of what we understand about placental function
relationship between death risk from cardiovascular disease has been discovered in animal models. The field of develop-
and birthweight among English men and women. They found mental origins of disease has gained enormous insight into
that term babies born at the 5 pound end of the birthweight the biological mechanisms that underlie developmental
scale had a 3e5 times greater risk for cardiovascular disease plasticity from animal studies. Langley-Evans et al14 were
compared with babies born at the 9 pound end. among the first to demonstrate that rat pups born to dams
Later it was discovered that there is an increasing risk for eating a low-protein diet during pregnancy had high blood
disease in term babies as their weights exceed the 9 pound pressure as adults. Dozens of additional studies using
birthweight at the high end of the birthweight scale.2-4 The different animal models have revealed the central role of the
discovery of the relationship between birthweight and later placenta.5,9,15-18
chronic disease stimulated extensive research among scientists Under adverse conditions, like poor maternal nutrition or
worldwide and brought to light a new level of understanding periods of chronic hypoxia, or high levels of thyroid hormone
regarding life-long health in offspring.5,6-10 The mechanism or glucocorticoids, the fetus suffers alterations in fetal organ
by which compromised development leads to adult onset structures including reduced coronary arterial dimensions,19
disease is called programming. low arterial elastin,20,21 reduced endowment of beta cells in
It was the unexpected trends in public health that brought the pancreas,22 decreased numbers of nephrons in the kid-
a new urgency to the concept of programming in the United ney23,24 and changes in brain structure and function.25 The
States. Beginning in the mid-1990s, the prevalence of obesity result is increased appetite, decreased cognitive function,
and type 2 diabetes began to rise in the Western world endothelial dysfunction, and compromised antioxidant pro-
in a dramatic way (http://www.cdc.gov/diabetes/statistics/ tection systems as well as dyslipidemias.26 The sum of these
prev/national/figpersons.htm). The upsurge in these 2 inter- effects leads to increased vulnerability for heart disease, dia-
related conditions, plus the ever-increasing numbers of peo- betes, stroke, and obesity for the remainder of an individual’s
ple who have uncontrolled blood pressure,11 led medical life.
scientists to predict that the current generation of young
people in the United States are likely to live shorter lives than The placenta as culprit
will their parents.12 Thus, it is now clear that patterns of growth and accommo-
The links between increasing prevalence of diseases like dations to maternal stress before birth are a major driver of
diabetes and heart disease and early life development are disease risk in offspring. The relationship between maternal
powerful and exist across mammalian species. Figure 1 shows dietary and tissue sources of nutrients, placental function,
the relationship between type 2 diabetes or insulin resistance and eventual embryonic and fetal growth is complex but not
and birthweight in which there is an 8-fold risk for diabetes well studied. Nevertheless, because the placenta is the source
across the birthweight scale. The relationship between of nutrients for the fetus, the provision of nutrients by the
birthweight and disease risk was so clear cut that Barker mother gives a central place to the placenta as a driver of
et al13 estimated that diabetes would be reduced by some 60% adult-onset disease.
The role of the placenta can be either active or passive. Low
From the Department of Medicine (Dr Thornburg), School of Medicine, rates of fetal growth are generally associated with reduced
Knight Cardiovascular Institute (Drs Thornburg and Marshall), Center for nutrient fluxes across the placenta. Furthermore, a long list of
Developmental Health, and Department of Obstetrics and Gynecology (Dr chronic diseases are associated with specific placental phe-
Thornburg and Marshall), Oregon Health and Science University, notypes.27 The transport of required nutrients from mother
Portland, OR.
to fetus requires optimal function of a myriad of separate
Received July 8, 2015; revised Aug. 7, 2015; accepted Aug. 10, 2015. transport mechanisms including the following: (1) diffusional
This work was supported by National Institutes of Health grants R01 permeability to blood gases,28-31 (2) transporters facilitating
AG032339, R01 HL102763, and P01 HD034430. K.L.T. was supported
diffusion of glucose and fatty acids,32-34 (3) active trans-
by the M. Lowell Edwards Endowment and N.M. was supported by grant
1K23HD069520. porters for amino acids and some ions,34-36 and (4) vesicular
Corresponding author: Kent L. Thornburg, PhD. [email protected]
transport systems that regulate the transport of iron and
immunoglobulins and many others.37,38 Thus, each of these
0002-9378/$36.00  ª 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2015.08.030 processes are known to be, or thought to be, associated with
compromised fetal growth.39

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Maternal stress and placental function

FIGURE 1
Fetal glucocorticoid levels increase toward the end of gesta-
Relationship between type 2 diabetes and
tion in a number of mammalian species including humans.40
birthweight
Glucocorticoids are important for the maturation of several
organs before birth including the lungs and heart, which
underlies the rationale for administration of corticosteroids to
women at risk for preterm delivery (reviewed by Challis et al,
200141). However, when maternal levels exceed those found
under normal physiological conditions, as during high levels
of social stress, glucocorticoids cross the placenta and cause
reduced fetal growth rates.42
An exception to the suppression of growth is found in the
heart in which cell proliferation and growth is stimulated by the
actions of glucocorticoids.43 In most cases of human intra-
uterine growth retardation, both maternal and fetal concen-
trations of circulating cortisol are elevated.44,45 Ordinarily active
cortisol in the human (and corticosterone in small mammals) is
inactivated in the placenta by 11b-hydroxysteroid dehydroge-
nase 2 (11b-HSD2), which catalyzes the rapid metabolism of
active cortisol and corticosterone to inert, inactive, 11-keto
forms. Unfortunately, when maternal levels exceed the rate of
inactivation in the placenta, active cortisol will cross the
placenta and exert programming effects on the fetus. Thus,
either elevated levels of maternal cortisol or reduced levels of The figure shows the relationship between the risk for impaired glucose
placental 11b-HSD2 will lead to programming in offspring. tolerance or type 2 diabetes and birthweight in 370 men aged
Expression levels of 11b-HSD2 are down-regulated by a approximately 64 years in Hertfordshire, United Kingdom (adjusted for
number of factors including sex steroids and hypoxia and up- body mass index).
Reproduced, with permission, from Hales et al.79
regulated by glucocorticoids themselves and cyclic adenosine
Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015.
monophosphate (reviewed by Seckl and Holmes, 20076).
Such offspring will have higher resting levels of cortisol as
adults46 and will have higher cortisol peaks during periods of
stress.47,48 Babies who were born small and had high gluco- than doubled.52 However, the placental response to the low
corticoid levels have elevated risks for chronic diseases later in muscle mass condition and the augmentation of inflamma-
life including hypertension, hyperinsulinemia, hyperglycemia, tory signals associated with obesity53 suggest the need for
and hyperactivity of the hypothalamic-pituitary-adrenal axis.6 more precise definitions of placental inflammation that are
not characterized by a full-blown immune response. This
Placental inflammation need has been suggested in cases of systemic inflammatory
There is increasing evidence that in addition to characteristic changes in cancer that stimulate known signaling cascades
inflammatory responses to infectious agents, placental but lack the full response seen in local hot inflammation in
inflammation that derives from maternal conditions such as which granulocytes accumulate.54
diabetes and obesity leads to fetal programming. Acute and We hypothesize that the known stressors that lead to fetal
chronic inflammation conditions in the placenta are associated programming, including poor nutrition, toxic social stress,
with fetal morbidity and mortality including preterm birth.49,50 and hypoxia, can alter immune function, reduce the actions
In addition to these nicely described categories, there may of protectants of oxidative stress, and lead to a cold form of
be milder forms of inflammation that do not fit easily under inflammation.54 Many of the same signaling pathways,
current definitions. O’Tierney et al51 showed that women including activation of activator protein-1, nuclear factor-
who lack muscle have placentas characterized by elevated kappa B, and interferon regulatory factors, mediate tissue
expression of proinflammatory genes. In this study, expres- responses in both hot and cold conditions. We speculate that
sion of interferon-gamma in the placentas of women who had the cold type of inflammation is often present in the human
low muscle mass was elevated, as were a host of placental placenta and that it mediates a persisting smoldering
target genes. However, there was no sign of classical inflam- inflammation in the fetus that makes it vulnerable for chronic
mation in the tissue. For example, neither T cells bearing CD3 disease over years in the future.
markers nor B cells (CD20), nor macrophages (CD68) nor
neutrophils (CD64) were elevated in these placentas. Plasticity of the placenta
The lack of cellular response contrasts the placentas from The team of Barker et al55 showed a U-shaped relationship
obese mothers in whom CD68- and CD14-positive cells more between cardiovascular death risk and the ratio of placental

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period. Thus, there seems to be a period of time when the

FIGURE 2 growth of the placenta responds to the demands placed on it.
Risk of coronary heart disease based on the ratio of When that period has passed, it can no longer accommodate
placental weight to birthweight the increasing demands for nutrients. This change in
placental plasticity will influence the fetal response to
maternal insults.

Placental lessons from the Helsinki birth cohort

Epidemiological studies demonstrate that a woman’s body
composition, including her relative fat, muscle, and pelvic
bone masses, are important regulators of placental function
and fetal outcomes.27,60 These epidemiological associations
and others suggest that maternal body composition affects
placentation.61 High BMI is associated with adverse preg-
nancy outcomes including preeclampsia, thromboembolism,
and gestational diabetes mellitus62,63 and has detrimental
effects on the fetus including macrosomia and preeclamp-
sia.64,65 Furthermore, babies born to obese mothers have a
The figure shows the risk of coronary heart disease based on the ratio of compromised immune system.66
placental weight to birthweight in an English population.80 Low placental The Helsinki birth cohort comprises 13,345 men and
weight to birthweight is defined as efficient and represented by the left- women born during 1934-194467,68 and an older cohort
hand bars. This U-shaped curve suggests that placental efficiencies are comprising 7086 people born during 1924-1933.69 The Hel-
related to the risk for disease. This relationship has been found in other sinki birth cohort is a gold mine for placentologists because at
studies as well.72 the time of birth, midwives and nurses measured the weights,
Reproduced, with permission, from Godfrey.8 widths, and lengths of all births in Helsinki hospitals during
Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015. those periods of time. Among w6000 placentas, the lengths
exceeded their widths by an average of 2.6 cm with the dif-
ference ranging from 0 to 21 cm. From these data and others,
it is now possible to link poor fetal growth and/or placental
weight to birthweight (Figure 2). Small placentas bearing phenotype with70 metabolic disease and obesity,71 coronary
large babies are defined as highly efficient and large placentas heart disease,72 heart failure,73 sudden cardiac death,55
bearing small babies are deemed inefficient. Figure 3 shows asthma,74 and osteoporosis75 as well as cancers including
the birthweight of some 17,000 placentas from babies born in Hodgkin’s lymphoma,76 lung cancer,77 and colorectal
Saudi Arabia according to their placental weight. In the upper cancer.78
left-hand quadrant are large babies born with small efficient
placentas; the lower right-hand quadrant shows small babies Placental thickness is associated with sudden cardiac death
born with large inefficient placentas. Among 187 men and 47 women, sudden cardiac death
Based on the placental ratios in the UK study,8 we can outside the hospital55 was associated with a thin placenta and
predict that the efficiency extremes of this population will had a hazard ratio of 1.47 (95% confidence interval,
carry elevated risks for chronic disease. We also know that 1.11e1.93) for every gram per square centimeter decrease in
boys tend to make placentas that are more efficient than do placental thickness. Sudden cardiac death is thought to be
girls.56,57 This may explain some of the differences in disease associated with excess sympathetic tone and subsequent
patterns between the sexes during adulthood. ventricular fibrillation. Thus, one can speculate that an
The regulation of growth of the placenta is not well un- inadequate placenta, perhaps caused by inadequate tropho-
derstood. It is well known that to grow heavier lambs, farmers blast invasion, compromised nutrient exchange and the
placed previously well-fed pregnant ewes on poor pasture development of the autonomic nervous system.
early in pregnancy to stimulate the growth of the placenta and
later returned the ewes to good pasture.58 Human placentas Chronic heart failure is associated with a small placenta
may also respond to inadequate nutrient delivery by Among 187 people in the Helsinki birth cohort of
expanding their tissue mass. 1934e1944, chronic heart failure was associated with a small
Data from nonhuman primates illustrate the loss of plas- surface area of the delivered placenta.73 In people who were
ticity of the placenta as a function of gestational age. When born with a placenta of <225 cm2, the odds ratio was 1.7
the bridge vessels between the 2 lobes of the rhesus placenta (95% confidence interval, 1.1e2.5) compared with people
are ligated, the nonligated primary lobe is able to compensate with larger placentas having a surface area of >295 cm2. Short
by enlargement.59 But this is true only at midgestation and placental width but not length also predicted the disease but
not if the vessels are ligated at or after 67% of the gestational only in short mothers.

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FIGURE 3
High- and low-efficiency placentas

This figure shows 17,000 live births in Unizah, Saudi Arabia. Boxes show quadrants of high- and low-efficiency placentas. Efficiency is the weight of
the placenta as a fraction of birthweight. This suggests that efficiencies at the extremes are associated with chronic disease.
Modified from Alwasel et al.81
Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015.

Other factors were also associated with heart failure. A disease (see Table); and (3) in tall mothers who were thin,
rapid gain in BMI between 2 and 11 years of age was also coronary heart disease was related to placental efficiency. The
associated with chronic heart failure, a path of growth that hazard ratio was elevated with an increase in the placental
has been associated with insulin resistance. It appears that the weight/birthweight ratio. Thus, there was a profound inter-
combination of a small placenta and rapid childhood weight action between maternal phenotype, placental deviation from
gain leads to poor glucose control, which predisposes to heart roundness, placental surface area at delivery, and placental
failure later in life. efficiency. These complex relationships suggest a profound
interaction between maternal body composition and
Coronary heart disease is associated with 3 different placental form and function as suggested by others.61
maternal/placental phenotypes
Among 7000 men born in the Helsinki birth cohort during Conclusions
1934e1944,72 those who developed coronary heart disease The placenta is at the center of the programming universe
were thin at birth and their disease was associated with the because fetal growth determines the degree of vulnerability
following 3 different placental/maternal phenotypes: (1) in that a neonate carries for adult onset disease. Stress, poor diet,
short primiparous mothers, the hazard ratio for coronary and hypoxia are major stressors that are mediated by the
disease was related to the difference between the length and placenta. When it comes to understanding the mechanisms
width of the placental surface; (2) in tall mothers whose BMI that regulate the growth and function of the placenta, we are
was above the median, a small placental surface predicted the stifled by ignorance. We can say with confidence, however,

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7. Myatt L. Placental adaptive responses and fetal programming.

TABLE J Physiol 2006;572(Pt 1):25-30.
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Placenta 2002;23(Suppl A):S20-7.
(>160 cm) according to her body mass index 9. McMillen IC, Robinson JS. Developmental origins of the metabolic
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£26 kg/m2 >26 kg/m2 571-633.
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Variable HR (95% CI) HR (95% CI)
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Placental weight, g cohort study. Am J Clin Nutr, in press.
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550 0.8 (0.4e1.3) 2.2 (1.3e4.0)
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