Endocrine-Related Causes and Consequences

of Intrauterine Growth Retardation

CHRISTINA KANAKA-GANTENBEIN,a GEORGE MASTORAKOS,b
AND GEORGE P. CHROUSOSa,c
aDepartment of Pediatric Endocrinology, 1st Department of Pediatrics, Agia Sofia

Childrens Hospital, Medical School, University of Athens, Athens, Greece

b2nd Department of Obstetrics and Gynecology, Aretaieion Hospital,

Medical School, University of Athens, Athens, Greece

cPediatric and Reproductive Endocrinology Branch, National Institute of Child Health

and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USA

ABSTRACT: The term intrauterine growth retardation (IUGR) is assigned to

newborns born with a birth weight and/or birth length below the tenth percentile for their gestational age. Intrauterine growth retardation is usually due to
maternal, fetal factors, or placental insufficiency, while endocrine factors represent just a small minority in its etiology. Main endocrine-related causes of
IUGR are disorders in insulin or insulin-like growth factor-I (IGF-I) secretion
or action. Newborns with IUGR are at increased risk to develop a metabolic
syndrome later in life, namely obesity, arterial hypertension, hypercholesterolemia, cardiovascular disease, impaired glucose tolerance, or diabetes mellitus type 2. This association is the result of the adaptational changes of the fetal
endocrinemetabolic mechanisms to the impaired intrauterine milieu to assure
survival in the short term. The persistence of these changes after birth can be
detrimental in adult life. Furthermore, premature adrenarche, as well as ovarian hyperandrogenism, seem to be associated with IUGR in girls, demonstrating that IUGR may have long-lasting effects on both somatic health and
reproductive function. Finally, the intrauterine exposure of the fetus to stressors may affect the individuals ability to face stress in postnatal life. Therefore,
if optimization of somatic and psychosocial well-being of the individual is the
golden goal of medicine, special attention should be paid to maintain an optimal intrauterine milieu devoid of any stressors with adequate nutrient supply
and to reserve ideal psychosocial support to the pregnant woman.
KEYWORDS: IUGR; SGA; fetal origin; adult disease; metabolic syndrome; insulin resistance; diabetes mellitus type 2; cardiovascular disease; premature
adrenarche; polycystic ovary syndrome

INTRODUCTION
Intrauterine life prepares a new organism to arrive mature in postnatal life and be
able to face postnatal insults. However, even during intrauterine life, the growing emAddress for correspondence: Dr. Med. Christina Kanaka-Gantenbein, Tymfristou 52-15234
Halandri, Athens, Greece. Voice: +30-210-7779909; fax: +30-210-6891366.
ganten@hol.gr

Ann. N.Y. Acad. Sci. 997: 150157 (2003). 2003 New York Academy of Sciences.
doi: 10.1196/annals.1290.017
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bryo may be exposed to various environmental influences that may determine both its
prenatal growth as well as its ability to react to various situations later in postnatal life.

NORMAL FETAL GROWTH

Normal fetal growth takes place in two different phases.1 The first phase consists
of the proliferation, organization, and differentiation of the embryo (embryonal life),
while the second phase (fetal life) consists of the continuing growth and functional
maturation of the different tissues and organs of the fetus.1 The main determinants
of fetal growth are the genetic output of the embryo, the right placentation, the integrity of the maternoplacentofetal unit, adequate nutrient and oxygen supply to
the developing fetus, and the right hormonal milieu.13 Inadequacy in one of these
parameters can lead to impaired fetal growth or induce intrauterine growth retardation (IUGR).14

INTRAUTERINE GROWTH RETARDATION

The term intrauterine growth retardation (IUGR), or small for gestational age
(SGA), is therefore assigned to newborns with a birth weight and/or birth length below the 10th percentile for their gestational age with pathologic restriction of fetal
growth due to adverse genetic or environmental influences.3,4 It is noteworthy that
the increase of different somatometric parameters of fetal growth, such as length and
weight, takes place during different stages of the intrauterine life. Growth in length
occurs early in prenatal life, while accumulation of weight occurs later during prenatal life.1 Therefore, there is a differential effect on weight or length of the newborn,14 depending on the period during intrauterine life when the adverse influence
is exerted on the fetus.1,3,4 We can therefore classify IUGR according to whether the
fetus has a symmetrical reduction of weight and length (symmetrical) or only of
weight while keeping an almost normal length (asymmetrical). This classification
demonstrates different etiopathogenetic mechanisms.3 Specifically, the asymmetrical type of growth retardation develops when oxygen or substrate supply to the fetus
is reduced during the last trimester of pregnancy mainly due to the reduced functional capacity of the placenta. Skeletal growth and brain growth are less affected, and
the newborns have a relatively normal head circumference, a pattern that has led to
the concept of adaptation that protects the growth of head and length.3,5,6 This is the
most frequent type of growth retardation, and is of extrinsic origin. Postnatal catchup growth is frequently observed.
The symmetrical intrinsic type of growth retardation is present in early pregnancy
and is multifactorial, most frequently being the result of genetic factors, congenital
infections, congenital syndromes, or toxic effects in early gestation.3 In that type,
cell division and cell growth are diminished, which affects various organs, for example, the nephrons7 or the pancreatic beta cells.8,9 Catch-up growth postnataly is rarely seen.

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CAUSES OF INTRAUTERINE GROWTH RETARDATION

The main causes of IUGR are intrauterine infections, genetic factors, uteroplacental insufficiency, and diseases of the mother such as chronic infections, eclampsia, and substance abuse.3,4,10
Regarding the etiologic factors responsible for IUGR, one third of the variations
in birth weight are determined by genetic variables, while two thirds are determined
by environmental factors. However, as many as 40% of IUGR cases have an unknown underlying cause.4 Endocrine-related causes constitute the minority of factors leading to IUGR.3,4 It is noteworthy that the main hormonal factors that
influence fetal growth are not related to the typical growth hormone (GH), which
plays a major role in postnatal growth. During fetal life, an adequate nutrient supply
mainly determines fetal growth, while the intervening growth factors have rather a
paracrine or autocrine role to play at the local level to assure the availability of a nutrient supply and to promote functional differentiation of the different tissues and organs.1,11 These growth factors are mainly insulin, the main anabolic hormone, and
the insulin-like growth factors IGF-I and IGF-II, while the role of other growth factors, such as EGF, TGB-, and leptin is less well documented in human fetal growth.
Deficiencies of these growth factors or impairment of their signaling pathway may
therefore lead to IUGR.1,11
Defects of insulin secretion or action, such as various causes of insulin resistance,
lead to impaired fetal growth.12,13 In cases of glucokinase deficiency due to mutations of the glucokinase gene, insulin secretion is decreased and newborns demonstrate IUGR.13 Furthermore, in cases of pancreatic agenesis, due to mutation of the
insulin promoter factor 1 (IPF1) gene, no secretion of insulin is observed, and the
affected newborns are significantly intrauterine growth retarded. Also in cases of
transient neonatal diabetes mellitus, because of isodisomy or duplication of the chromosome 6 at position 6q22-q33, the secretion of insulin is significantly compromised and the affected newborns show severe IUGR. On the other hand, in
leprechaunism, a syndrome of extreme insulin resistance due to insulin-receptor mutation, insulin levels are high and the birthweight of the newborns is severely reduced
due to insulin signaling pathway dysfunction.12 Furthermore, as far as IGF-I is concerned, it has been reported that IGF-I gene deletion in man leads to significant
IUGR, neurosensorial deafness, and mental retardation.14 Also, it was reported that
polymorphisms of the IGF-I gene are associated with IUGR.1416
IUGR AND THE METABOLIC SYNDROME
Since the late 1980s, many papers have been published in the international literature that demonstrate an association between IUGR and the later development of
the metabolic syndrome, comprising arterial hypertension, hypercholesterolemia,
impaired glucose tolerance, and diabetes mellitus type 2 in mostly obese adults.1727
This observation, which originated at Hertfordshire in the UK,1720 was subsequently confirmed in other countries such as Sweden,23 Holland,24 and more recently in India,25 South Africa,26 and other developing countries, where obesity is not a
great problem. As a possible explanation for this association, it has been suggested,
that in the case of an impaired intrauterine milieu, such as nutrient restriction, the

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adverse intrauterine environment causes a reprogramming of the endocrine

metabolic status of the fetus, which has short-term survival benefits. This hypothesis, which is widely approved by the international scientific community, is known as
the thrifty phenotype hypothesis or Barkers hypothesis, after its founder David
Barker.1720,28,29 According to this hypothesis, this reprogramming of the endocrinemetabolic status may be, however, detrimental in the long term, if the prenatal
nutrient restriction is subsequently followed by an extrauterine nutrient abundance,
thus leading to development of the metabolic syndrome. In other words, every cause
of IUGR can be considered to have an endocrine-related cause, since it induces a reprogramming of the endocrinemetabolic milieu of the fetus in order to allow survival in the short term.
This reprogramming consists mainly of the development of insulin resistance,
which in turn induces the other components of the metabolic syndrome.3034 What
is the underlying pathogenetic mechanism of this insulin resistance? It seems that the
adverse intrauterine environment causes the hypothalamicpituitaryadrenal (HPA)
axis to overact by changing its set point, which leads to increased cortisol
levels, 3539 both spontaneously and after ACTH stimulation, a situation resembling
that seen in chronic stress.37,40 This overactivation of the HPA axis has been demonstrated both in experimental animals and in newborns with IUGR, both of which
have increased cortisol levels in umbilical cord blood. These IUGR newborns persistently demonstrate increased cortisol excretion in urine in childhood,41,42 as well
as increased morning cortisol levels during young adulthood.26 The increased cortisol levels during intrauterine life induce both the endothelial damage, which is responsible for the later development of cardiovascular disease, and the development
of insulin resistance, which is responsible for the other parameters of the metabolic
syndrome.35,36,43
Moreover, it is noteworthy that, depending on the time when the intrauterine restriction occurred, the individual has a different risk of developing one of the parameters of the metabolic syndrome. Namely, newborns with the symmetric type of
IUGR are more at risk of developing arterial hypertension later in life,19,23,25,27,38
while newborns with the asymmetric type of IUGR are more at risk of developing
glucose intolerance and diabetes mellitus type 2.29,31,32
IUGR AND PSYCHOSOCIAL ADJUSTMENT
Moreover, there is a lot of evidence that this overactivation of the HPA axis can
have long-lasting effects on the individuals ability to face stress, and that persons
exposed to intrauterine malnutrition demonstrate a higher incidence of antisocial behavior or even schizoid personality. In other words, it seems that intrauterine life exerts a long-lasting effect on both the somatic and psychological health of the
individual.44,45
IUGR AND REPRODUCTIVE FUNCTION
Besides the association of IUGR and the development of the metabolic syndrome
or affective disorders, recent papers also documented the association between IUGR

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and premature adrenarche in girls, as well as the higher incidence of functional ovarian hyperandrogenism and the development of the polycystic ovary syndrome in
these girls in young adulthood.4650 It has been shown that, compared to adequate
for gestational age-born (AGA) girls, IUGR girls have higher levels of DEHA-S, a
marker of adrenarche, at the same prepubertal age, indicating the onset of premature
adrenarche in IUGR girls.46,48,51 Insulin resistance again was shown to be the key
factor in these associations.47,50
These observations, which are based mainly on north Hispanic girls born small
for their gestational age, have not always been confirmed in other large studies. In
fact, in a large Dutch study no association was found between IUGR and premature
adrenarche.52 Furthermore, although the higher insulin levels found in north Hispanic IUGR girls47 have been confirmed in a French IUGR study, hyperandrogenism
was not found to be a consistent association in those IUGR girls.53
Papers dealing with the question of pubertal onset in formerly IUGR children
present contradictory results. Therefore, puberty in IUGR children has been reported
to occur either earlier,54 or at the lower limit of the physiologically expected age,53
or even later than in AGA children.55
Another important issue is that of the reduced uterine volume and smaller fraction
of ovarian follicles observed in IUGR girls,54,56 both of which may have a negative
impact on the future fertility of these women. It therefore seems that the associations
between IUGR and the reproductive axis in IUGR born women, although not totally
clarified as yet, deserve special attention in order to assure the best intrauterine conditions for a long healthy life, devoid of morbidity or reproductive dysfunction.
CONCLUSIONS
In conclusion, an adverse intrauterine milieu and IUGR may cause the development of a metabolic syndrome and personality dysfunction, as well as reproductive
dysfunction, in the adult lives of affected females. In order to avoid the long-lasting
economic and psychological burden of the metabolic syndrome, affective disorders,
and reproductive dysfunction, special attention therefore should be paid to optimization of the intrauterine environment by providing the ideal nutrient supply to the
fetus and the best possible psychosocial support to the pregnant woman.
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