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Fetal Origins of Adult Disease

Rebecca Simmons

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Objectives
After completing this article, readers should be able to:
1. Define programming.
2. List the adult diseases that have been linked epidemiologically with low birthweight.
3. Describe the fetal insulin hypothesis.
4. Delineate the cellular consequences of fetal malnutrition.
5. Describe the vulnerabilities of beta cells that may occur in the fetal-neonatal period.

Programming
The period from conception to birth is a time of rapid growth, cellular replication and
differentiation, and functional maturation of organ systems. These processes are very sensitive to

alterations in the intrauterine milieu. Programming describes the mechanisms whereby a stimulus
or insult at a critical period of development has lasting or lifelong effects.

Epidemiology
It has been recognized for nearly 70 years that the early environment in which a child grows and
develops could have long-term effects on subsequent health and survival. As discussed in the
article by Matharu and Ozanne in this issue of NeoReviews, multiple epidemiology studies have
linked low birthweight to the later development of a number of adult diseases, including
hypertension, coronary artery disease, stroke, diabetes, kidney disease, and breast cancer. Studies
controlling for the confounding factors of socioeconomic status and lifestyle factors have
strengthened the association further of low birthweight with increased risk of coronary heart
disease, stroke, and type 2 diabetes. In 1976, the Nurses Health Study was initiated, and a large
cohort of United States women born from 1921 to 1946 was established. The associations of low
birthweight with increased risk of coronary heart disease, stroke, and type 2 diabetes remained
strong in this cohort, even after adjusting for lifestyle factors such as smoking, physical activity,
occupation, income, dietary habits, and childhood socioeconomic status.

The Role of Catch-up Growth

Many studies have suggested that the associations of birth size with later disease are modified by
body mass index (BMI) in childhood. The highest risk for the development of type 2 diabetes is
among adults who were born small and become overweight during childhood. Insulin resistance
was shown to be most prominent in Indian children who were born small for gestational age but
had a high fat mass at 8 years of age. Similar findings were reported in 10-year-old children in
the United Kingdom. In a Finnish cohort, adult hypertension was associated with both lower
birthweight and accelerated growth in the first 7 years of life. In contrast, two recent preliminary
studies from the United Kingdom showed that catch-up growth in the first 6 months of life
clearly was not related to young adult blood pressure, although birthweight was.
Interpretation of these studies is complicated by the vague definitions of catch-up growth. Catchup growth can encompass the first 6 to 12 months to as late as 2 years after birth and usually
refers to realignment of a persons genetic growth potential after intrauterine growth retardation
(IUGR). This definition allows for fetal growth retardation at any birthweight; even large fetuses
can be growth-retarded relative to their genetic potential.
However, postnatal factors obviously can affect infant growth in the first few postnatal months.
For example, breastfeeding appears to protect against obesity later in childhood, yet breastfed
infants usually exhibit higher body mass during the first postnatal year compared with formulafed infants. Although it is likely that accelerated growth confers an additional risk to the growthretarded fetus, the previously noted conflicting results demonstrate the need for additional
carefully designed studies to determine just how childhood growth rates affect the later
development of cardiovascular disease and type 2 diabetes.

Size at Birth and Insulin Secretion and Insulin Action

The mechanisms underlying the association between size at birth and impaired glucose tolerance
or type 2 diabetes are unclear. A number of studies in children and adults have shown that
nondiabetic or prediabetic people who had low birthweights are insulin-resistant and, thus,
predisposed to development of type 2 diabetes. IUGR is known to alter the fetal development of
adipose tissue, which is linked closely to the development of insulin resistance. In a welldesigned case-control study of 25-year-old-adults, individuals born small for gestational age
(SGA) at 37 weeks or more gestation had a significantly higher percent body fat. Insulin
sensitivity, even after adjusting for BMI or total fat mass, was impaired markedly in these
individuals. There were no significant differences between the SGA and control groups with
respect to parental history of type 2 diabetes, cardiovascular disease, hypertension, or
dyslipidemia. Of importance to generalizing the findings to other populations, the causes of
IUGR were gestational hypertension (50%), smoking (30%), maternal short stature (7%),
congenital anomalies (7%), and unknown (6%).
Originally, it was believed that the adverse effect of IUGR on glucose homeostasis was mediated
through programming of the fetal endocrine pancreas. IUGR fetuses and newborns have been
shown to have a reduced population of pancreatic beta-cells. Low birthweight has been
associated with reduced insulin response after glucose ingestion in young nondiabetic men,
although a number of other studies have found no impact of low birthweight on insulin secretion
in humans. However, none of the earlier studies adjusted for the corresponding insulin
sensitivity, which has a profound impact on insulin secretion. Therefore, Jensen and colleagues
measured insulin secretion and insulin sensitivity in a well-matched Caucasian population of 19year-old glucose-tolerant men whose birthweights had been either below the 10th percentile
(SGA) or between the 50th and 75th percentiles (controls). To eliminate major confounders such
as diabetes genes, none of the participants had a family history of diabetes, hypertension, or
ischemic heart disease. There was no difference between the groups with regard to current
weight, BMI, body composition, and lipid profile. When controlled for insulin sensitivity, insulin
secretion was reduced by 30%. However, insulin sensitivity was normal in the SGA study
participants. The investigators hypothesized that defects in insulin secretion may precede defects
in insulin action and that once SGA individuals accumulate body fat, they develop insulin
resistance.

Epidemiologic Challenges
These data suggest that low birthweight is associated with glucose intolerance, type 2 diabetes,
and cardiovascular disease. However, the question remains as to whether these associations
reflect fetal nutrition or other factors that contribute to birthweight and the observed glucose
intolerance. Because of the retrospective nature of the cohort identification, many confounding
variables were not recorded regularly, such as lifestyle, socioeconomic status, education,
maternal age, parental build, birth order, obstetric complications, smoking, and maternal health.
Maternal nutritional status, either directly in the form of diet histories or indirectly in the form of
BMI, height, and pregnancy weight gain, usually was not recorded. Instead, birth anthropometric
measures were used as proxies for presumed undernutrition in pregnancy.

Size at Birth Cannot be Used as a Proxy for Fetal Growth

Birthweight is determined by the sum of multiple known and unknown factors, including
gestational age, maternal age, birth order, genetics, maternal prepregnancy BMI, and pregnancy
weight gain, plus multiple environmental factors such as smoking, drug use, infection, and
maternal hypertension. Some of these determinants may be related to susceptibility to adult
disease, and others may not. Conversely, some prenatal determinants of adult outcomes may not
be related to fetal growth. A good example of size at birth having the potential to be a good proxy
for an underlying causal pathway is the hypothesis that essential hypertension in the adult is due
to a congenital nephron deficit. A recent study has shown that kidney volume is smaller in adults
who were thinner at birth, after adjustment for current body size. In contrast, maternal smoking is
a good example of a prenatal exposure that restricts fetal growth, but no association has been
found to date with adverse long-term outcome in the offspring.

Genetics Versus Environment

Several epidemiologic and metabolic studies of twins and first-degree relatives of patients who
have type 2 diabetes have demonstrated an important genetic component of diabetes. The
association between low birthweight and risk of type 2 diabetes in some studies theoretically
could be explained by a genetically determined reduced fetal growth rate. In other words, the
genotype responsible for type 2 diabetes itself may cause retarded fetal growth in utero. This
forms the basis for the fetal insulin hypothesis, which suggests that genetically determined
insulin resistance could result in low insulin-mediated fetal growth in utero as well as insulin
resistance in childhood and adulthood. Insulin is one of the major growth factors in fetal life, and
monogenic disorders that affect fetal insulin secretion or fetal insulin resistance also affect fetal
growth.
Obviously there is a close relationship between genes and the environment. Not only can
maternal gene expression alter the fetal environment, but the maternal intrauterine environment
also affects fetal gene expression. An adverse intrauterine milieu is likely to have profound longterm affects on the developing organism that may not be reflected in birthweight.

Cellular Mechanisms
Fetal malnutrition has two primary causes: poor maternal nutrition and placental insufficiency. In
the extensive literature about the fetal origins hypothesis, these two concepts have not been
discerned clearly. Such a distinction is, however, necessary because it is likely that maternal
nutrition has been adequate in most populations in which the hypothesis has been tested. Only
extreme maternal undernutrition, such as occurred in the Dutch famine, reduces the birthweight
to an extent that would be expected to increase the risk of adult disease. Thus, it is reasonable for
placental insufficiency to be a major cause of low birthweights in these populations. The oxygen
and nutrients that support fetal growth and development rely on the entire nutrient supply line,
beginning with maternal consumption and body size, but extending to uterine perfusion,
placental function, and fetal metabolism. Interruptions of the supply line at any point could result
in programming the fetus for future risk of adult diseases.

The intrauterine environment influences development of the fetus by modifying gene expression
in both pluripotential cells or terminally differentiated, poorly replicating cells. The long-range
effects on the offspring (into adulthood) depend on the cells undergoing differentiation,
proliferation, or functional maturation at the time of the disturbance in maternal fuel economy.
The fetus also adapts to an inadequate supply of substrates (such as glucose, amino acids, fatty
acids, and oxygen) by metabolic changes, redistribution of blood flow, and changes in the
production of fetal and placental hormones that control growth.
The immediate metabolic response of the fetus to placental insufficiency is catabolism; it
consumes its own substrates to provide energy. A more prolonged reduction in the availability of
substrates leads to a slowing in growth. This enhances the fetus ability to survive by reducing
the use of substrates and lowering the metabolic rate. Slowing of growth in late gestation leads to
disproportion in organ size because organs and tissues that are growing rapidly at the time are
affected the most. For example, placental insufficiency in late gestation may lead to reduced
growth of the kidney, which is developing rapidly at that time. Reduced replication of kidney
cells may reduce cell numbers permanently because after birth there seems to be no capacity for
renal cell division to catch up.
Substrate availability has profound effects on fetal hormones and on the hormonal and metabolic
interactions among the fetus, placenta, and mother. This is most apparent in the fetus of the
mother who has diabetes. Increased maternal concentrations of glucose and amino acids
stimulate the fetal pancreas to secrete exaggerated amounts of insulin and the fetal liver to
produce higher levels of insulin-like growth factors (IGFs). Fetal hyperinsulinism stimulates the
growth of fetal adipose tissue and of other insulin-responsive tissues, often leading to
macrosomia. However, many offspring of diabetic mothers who have fetal hyperinsulinism are
not overgrown by usual standards, and many who later exhibit obesity and glucose intolerance
were not macrosomic at birth. These observations suggest that birthweight is not a good
indication of intrauterine nutrition.

What Can Animal Models Tell Us?

Animal models have a normal genetic background on which environmental effects can be tested
for their role in inducing diabetes. In the rat, maternal dietary protein restriction (approximately
40% to 50% of normal intake) throughout gestation and lactation has been reported to cause
altered glucose homeostasis and hypertension in the adult offspring. Offspring exhibit significant
growth retardation, remain growth-retarded throughout life, and in some cases develop mild beta
cell secretory abnormalities or insulin resistance.
To extend these experimental studies of growth retardation, a model of IUGR in the rat was
developed that leads to diabetes in later life. This model of fetal growth retardation has many
advantages: 1) bilateral uterine artery ligation induces uteroplacental insufficiency, one of the
most common causes of human IUGR; 2) growth-retarded fetal rats have critical features of a
metabolic profile characteristic of growth-retarded human fetuses, including decreased levels of
glucose, insulin, IGF-I, amino acids, and oxygen; and, most importantly, 3) IUGR rats develop
diabetes that has a phenotype remarkably similar to that observed in the human who has type 2
diabetes: progressive dysfunction in insulin secretion and insulin action. Because of this IUGR

models similarity to human growth retardation and subsequent disease states, the IUGR rat
represents one of the best experimental tools for studying the impact of uteroplacental
insufficiency on the evolution of diabetes.
Although insulin resistance is a critical component of human type 2 diabetes, it is the failure of
beta cell function and growth that determines progression to the diabetic phenotype. Most
pancreatic islet growth takes place during the fetal-neonatal period, but replication of existing
beta cells and neogenesis of precursor cells occurs throughout life. It is hypothesized that
insufficient proliferation and neogenesis is the underlying cause of the lack of beta cell
compensation that leads to type 2 diabetes. Thus, uteroplacental insufficiency during the last
trimester in the fetus permanently impairs the processes of neogenesis, proliferation, and
differentiation. If new beta cells are not generated to replace the normal loss of existing beta
cells, eventually the beta cell mass will be reduced and diabetes will ensue.
Beta cells are particularly vulnerable to changes in substrate and hormone availability. Indeed,
SGA infants have reduced plasma insulin concentrations and pancreatic beta cell numbers,
whereas beta cell growth is enhanced in the fetus exposed to excess nutrients and hormones in
the diabetic milieu of diabetes in pregnancy.
A major consequence of uteroplacental insufficiency is oxidative stress in the fetus. Decreased
substrate supply alters the redox state in susceptible tissues, leading to an imbalance between the
production of reactive oxygen species and antioxidant capacity that results in mitochondrial
dysfunction and oxidative stress. The beta cell is particularly vulnerable to oxidative stress
because expression of antioxidant enzymes in the pancreatic islets is very low, and the pancreas
has a high oxidative energy requirement. Animal studies in the IUGR rat support the concept that
oxidative stress plays a major role in the impaired beta cell function and maturation that is
observed in the human growth-retarded fetus.

Conclusion
Epidemiologic, clinical, and animal studies clearly demonstrate that the intrauterine environment
influences both growth and development of the fetus and the subsequent development of adult
diseases. There are critical specific windows during development, often coincident with periods
of rapid cell division, during which a stimulus or insult may have long-lasting consequences on
tissue or organ function postnatally. Birthweight is only one marker of an adverse fetal
environment, and confining studies to this population may lead to erroneous conclusions
regarding causation. Studies using animal models of uteroplacental insufficiency can provide
some insight into possible mechanisms underlying the fetal origins hypothesis, but much work
remains.

Copyright 2004 by the American Academy of Pediatrics

Suggested Reading

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children: small at birth, big at 8 years, or both? Diabetes. 1999;48:24222429
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Birthweight and adult hypertension, diabetes mellitus and obesity in US men.
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born small for gestational age: regional cohort study. BMJ. 1997;315:341347
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defects of insulin secretion and action in 19-year-old Caucasian men who had low birth
weight. Diabetes. 2002;51:12711280
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influences adult blood pressure? Pediatr Res. 2001;50:11A
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diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype. BMJ.
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8. Ozanne SE, Wang CL, Coleman N, Smith GD. Altered muscle insulin sensitivity in the
male offspring of protein-malnourished rats. Am J Physiol. 1996;271:E1128E1134
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diabetic Pima Indian women despite normal birth weight. Diabetes Care. 1987;10:7680
10. Simmons RA, Templeton L, Gertz S, Niu H. Intrauterine growth retardation leads to type
II diabetes in adulthood in the rat. Diabetes. 2001;50:22792286
11. Singh GR, White AV, Spencer J, Hoy WE. Intrauterine growth influences kidney size and
function: the renal dimension of the fetal origins hypothesis. Pediatr Res. 2001;20:30A
12. Speizer FE, Manson JE. Birthweight and the risk for type 2 diabetes mellitus in adult
women. Ann Intern Med. 1999;130:278284
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health outcomes in a biethnic population in the USA. Diabetologia. 1994;37:624531
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