Journal of Pediatric Endocrinoloby & Metabolism 2002; 15:1479-86
BIRTH SIZE AND NEONATAL LEVELS
OF MAJOR COMPONENTS OF THE IGF SYSTEM:
IMPLICATIONS FOR LATER RISK OF CANCER
Skalkidou A1, Petridou E1,2, Papathoma E3, Salvanos H4, Chrousos G5, Trichopoulos D1, 2
1. Department of Hygiene and Epidemiology, Athens University Medical School,
M.Asias 75, Athens 11527, Greece
2. Department of Epidemiology, Harvard School of Public Health, 677 Huntington
Avenue, Boston, Massachusetts 02115, USA
3. Department of Neonatology, “Alexandra Hospital”, 80, Vas.Sofias ave, Athens
11528, Greece
4. Department of Neonatology, “Marika Iliadi” Maternity Hospital, Plateia El.
Venizelou, Athens11521, Greece
5. First Department of Pediatrics, Athens University Medical School, 3, Thivon st,
Athens, 11527, Athens, Greece
Address for correspondence and reprints:
Eleni Petridou, MD
Department of Hygiene and Epidemiology
Athens University Medical School
75 M. Asias Str. Goudi, Athens 11527
Tel : +3010-7462105 Fax : +3010-7773840
E-mail : epetrid@med.uoa.gr
Abstract
Pre- and perinatal conditions and processes may affect the risk of some forms of cancer
in later life, while the insulin-like growth factor (IGF) system may play a role in both
early somatic growth and later carcinogenesis. Birth weight and length, and the
variation of major components of the IGF system immediately after birth, were
analyzed in relation to selected physiologic and pathologic variables. The study
comprised 331 healthy full-term newborns from which blood samples were taken during
routine phlebotomy no later than the fifth day of life. Measurements of IGF-I, IGF-II
and IGF-binding protein-3 concentrations were performed. Birth length and weight
were measured and information on socioeconomic and medical variables was recorded.
The concentrations of all 3 proteins were lower when blood bilirubin levels were high,
possibly as a result of compromised liver function and/or as component of an activated
acute phase reaction. Birth weight was significantly higher by about 46g among
children whose IGF-I was higher by one standard deviation, while the associations of
birth weight and length with other components of the IGF system were in the predicted
directions albeit, only in trend. We conclude that in early life, growth is related to the
IGF system, mostly IGF-I. The latter is lower in children with jaundice, possibly
because of hepatic dysfunction and/or as part of an acute phase reaction. We speculate
that elevations of IGF-I in early life might explain the increased risk of cancer in
individuals born with a higher birth weight.
Key-words: newborn, birth weight, insulin-like growth factor, jaundice, neoplasia
2
Introduction
Birth weight is a variable of central importance in perinatal epidemiology 1,2.
During the last three decades, however, it has also received attention as a predictor of
adult onset conditions like metabolic and cardiovascular diseases 3, and some forms of
neoplasias, including breast cancer 4, 5. On the other hand, evidence has emerged that
one or more components of the insulin-like growth hormone (IGF) system may be
intimately linked to the process of carcinogenesis in the prostate, breast, and, perhaps,
other body sites 6-10. Given the long latency of most forms of cancer, many authors have
become interested in a possible link between perinatal variables, birth size parameters
and one of more components of the IGF system.
Previous studies have reported a positive association between birth weight and
IGF-I plasma concentrations, and this was interpreted as supporting the hypothesis that
early life IGF- linked events and conditions may affect cancer risk in adult life.11-19 The
purpose of this investigation was to further examine whether birth size parameters,
including length and weight, are associated with components of the IGF system, and
whether immediate postnatal IGF levels in the newborn are as important as prenatal
levels measured in umbilical cord blood or in blood from the mother during pregnancy.
We studied a large group of full-term newborns in Athens, Greece, in whom we
measured the levels of IGF-I, IGF-II and IGF-binding protein-3 (IGF-BP3). In pilot
studies, IGF-I was strongly and inversely associated with blood bilirubin levels.20
Because of this, we performed our analysis by classifying our newborns in two
subgroups, one with clinical jaundice and blood bilirubin levels >12 mg/dl and the other
without clinical jaundice and blood bilirubin levels <8 mg/dl. This investigation is
unique in that the IGF-system components were measured in the blood from newborns
3
rather than in the umbilical cord. Only one earlier investigation followed this approach,
but it was somewhat smaller and had a different focus.21
4
Subjects and Methods
During the twelve-month period of 1999 approximately 6 000 and 4 000
newborns respectively, were delivered in the two University associated, major public
Maternity Hospitals in the Greater Athens area, Greece. Because in these hospitals
services are provided free of charge many of the attending pregnant women belong to
communities of temporary residents mainly originating from Albania, Poland, Bulgaria
and other countries of Eastern Europe. In order to be included in the study the newborn
had to be full term (≥37 weeks) with a birth weight of ≥2 500g, Caucasian, apparently
healthy, that is without serious symptoms or need for a Neonatal Intensive Care Unit
attendance. Moreover, they had to be born to women who did not suffer chronic disease
problems, such as cancer, connective tissue disorders, diabetes mellitus - unless it was
pregnancy related, anemia - unless it was pregnancy related, major neuropsychiatric
disorders (e.g. epilepsy and psychoses), chronic renal failure, peptic ulcer, ulcerative
colitis, bronchial asthma requiring treatment and chronic infectious diseases, including
hepatitis B and C. During the days when the two collaborating senior neonatologists
were in charge, i.e. about twice per month, eligible newborns were enrolled in the study
with consent of their mothers. Some 60 newborns were excluded for technical reasons or
because their mothers could not adequately communicate in Greek. Completed maternal
questionnaires and laboratory determinations were eventually available for a total of 331
newborns, who were bled during the morning, always in conjunction with routine
bleeding and no later than the fifth day of their life.
All determinations of the major IGF system components examined in this study
(IGF-I, IGF-II, IGF-BP3), as well as liver function determinations, were done in coded
frozen blood samples, blind as to the jaundice status by a major internationally certified
5
laboratory (BIOMED) in Athens. IGF-I was run on the Nichols AdvantageTM Automated
Specially System (Nichols Institute, San Juan Capistrano, CA). No cross-reactivity with
IGF-II, Pro-Insulin, Insulin, TSH or LH was detected. The sensitivity of the assay was
6ng/ml. IGF-II was determined by using the DSL-2600 ACTIVETM Non-Extraction
Insulin-Like Growth Factor-II Coated-Tube Immunoradiometric Assay Kit. The
procedure employs a two-site immunoradiometric assay (IRMA). The DSL-2600
ACTIVETM IGF-II IRMA includes a simple extraction step in which IGF-II is separated
from its binding protein in serum The IRMA is a non-competitive assay in which the
analyte to be measured is “sandwiched” between two antibodies. The first antibody is
immobilized to the inside walls of the tubes. The other antibody is radiolabelled for
detection. The analyte presents in the unknowns, standards and controls is bound by both
of the antibodies to form a “sandwich” complex. Unbound materials are removed by
decating and washing the tubes. The sensitivity was 12ng/ml. IGFBP-3 concentrations
(in µg/ml) were measured, using a commercially available radioimmunoassay kit
(IFGBP-3100T kit Nichols Institute, San Juan Capistrano, CA). During a single
incubation period radiolabeled IGF-BP3 completes with unlabeled IGFBP-3 in the test
sample, standards and controls for a limited number of specific antibody binding sites.
At the end of the incubation period antibody –bound IGF-BP-3 is separated from free
IGF-BP3 using anti-rabbit antisera. Following a brief incubation and centrifugation the
unbound IGF-BP3 is aspirated and the antibody-bound radiolabeled IGF-BP3 is
measured in a gamma counter. As the concentration of IGF-BP3 in the test sample
standard, or controls increases, the amount of antibody-bound radiolabeled tracer
measured decreases. A standard curve is prepared using this dose-response relationship
6
and test sample and controls concentration are read from the curve. The sensitivity of the
assay was 0.0625 µg/ml.
The analysis was initially done through simple cross tabulations. Subsequently,
the data were modeled through multiple regression with birth weight and birth length,
alternatively, as dependent variables.
7
Results
Table 1 shows the distribution of 331 full term newborns by selected
demographic and biosocial variables. Notable results in this table are the high
proportion of newborns from mothers who are temporary residents in this country and
the high prevalence of smoking during pregnancy.
Table 2 shows mean values and standard errors of perinatal characteristics and
the measured hormones of the IGF system by gender as well as by presence of jaundice
in the newborn. IGF-I, IGF-II and total blood proteins among both boys and girls are all
significantly higher when blood bilirubin levels are low and clinical jaundice is absent.
These findings are likely to reflect the liver function. Indeed, the length of the newborn
is higher among those with low levels of blood bilirubin and without clinical jaundice
among both boys and girls; for birth weight the pattern is similar but statistically non
significant. These findings taken at face value provide group (ecological) evidence of
concomitant variation between IGF components on the one hand and birth length on the
other.
Table 3 shows multiple regression-derived mutually adjusted, changes of birth
length and weight by specified changes in a series of maternal and newborn
characteristics, including blood values of components of the IGF system. With respect
to birth length, associations with maternal and newborn characteristics are generally
compatible with what is known from the literature, although results are not always
statistically significant. Thus, birth length is higher among boys than among girls and
increases with more advanced gestational age and lower blood bilirubin levels. IGF-I
tends to be positively associated with birth length but the association is weak and
statistically non significant.
8
With respect to birth weight, most results are compatible with expectations.
Thus, birth weight was higher among boys than among girls, increased with gestational
age, was higher among newborns born to heavier mothers, and lower among children
whose mothers smoke. Moreover, birth weight was higher by about 46g among children
whose IGF-I was higher by one standard deviation.
9
Discussion
Neonatal jaundice was inversely correlated with birth length and similarly but
not significantly with birth weight. Smaller, jaundiced newborns had lower levels of
total plasma proteins, as well as IGF-I, IGF-II, and, at least among girls, IGF-BP3. Most
likely, these results reflect compromised liver function in smaller newborns with
hyperbilirubinemia and/or suppression of the IGF-I system as a negative component of
the acute phase reaction. It is also possible, but less likely, that the smaller newborn
group might include a relatively high proportion of those born after mild pre-eclampsia,
a condition with a systemic inflammatory component that activates the acute phase
reaction and leads to decreased production of IGF-I 22.
Levels of IGF-I and IGF-BP3 tended to be higher in female than male
newborns. A similar tendency of IGF-I to be higher in neonatal or umbilical cord blood
or blood obtained in childhood or adolescence in females than males has been reported
by other investigators. This may be a result of a possible effect of estrogens on the
growth hormone- IGF-I axis 19.
The results of this study concerning the association of socio-demographic
variables with birth weight and length are generally in accordance with those of the
existing rich literature on this subject23-25. Indeed, the compatibility of the observed
pattern of associations of birth size with socio-demographic variables with that expected
from the literature provides indirect support for the validity of the IGF related findings.
The findings of this investigation indicate that even at the earliest post-natal
stage of life, IGF-I is more important than IGF-II as a growth-promoting factor.
Although the IGF-I results were statistically significant only with respect to birth weight
and not length it is not possible to reject a generalized effect of IGF-I on growth. The
10
regression co-efficient for birth length (0.14 cm per one standard deviation of IGF-I) is,
in proportional terms, less than 20% of the regression co-efficient for birth weight (46.4
g per one standard deviation). Thus, 0.14 divided by the average length of 50cm equals
3‰, whereas 46.4 divided by the average 3000g equals 5‰. Birth length variability,
however, was considerably smaller than birth weight variability. The results of this
investigation also do not refute the hypothesis that IGF- BP-3 modulates the effect of
IGF-I by regulating the availability of free IGF-I.
Because of the different days of blood sampling after birth, there is
increased variability in the values of the measured components, but this has been
accommodated by introducing day of sampling in the statistical models. The cross
sectional design of this investigation imposes some constraints on etiologic inferences,
however the study also has considerable advantages. Subject selection, information
collection and laboratory analyses were performed under strict criteria and the postnatal
collection of blood samples provided a complementary perspective to a number of
investigations that were previously undertaken on umbilical cord blood with largely
similar results.
The overall evidence allows some firm conclusions and some plausible
speculation. It appears reasonable to conclude that IGF-I and, perhaps, IGF-II are
important factors in intra-uterine growth11-19. Since intrauterine growth appears to play a
role in some forms of cancer, notably breast cancer5,29 and childhood leukemia26-28 and
the IGF system has been implicated in the pathogenesis of these and other forms of
cancer, 6-9 it is reasonable to speculate that the IGF system and in particular IGF-I may
play a crucial role in the increased risk that heavier newborns have to develop some
forms of cancer in mid and late adult life.
11
Acknowledgements
The authors would like to thank Mr. N. Dessypris for his assistance in the statistical
analysis.
12
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17
Table 1: Distribution of 331 newborns by selected demographic and biosocial
variables (Athens, 1999/ Two maternity hospitals)
Variable
N
%
<25 years
105
31.7
25-34
181
54.7
45
13.6
110
33.2
10-12
129
39.0
13-15
43
13.0
16+
49
14.8
Greek or E.U.
192
58.0
migrants
139
42.0
112
33.8
140
42.3
79
23.9
no
260
78.5
yes
71
21.5
female
160
48.3
male
171
51.7
37-38 weeks
42
12.7
38
99
29.9
39
95
28.7
40
79
23.9
41+
16
4.8
Maternal age
35+
Maternal education
9
years
Ethnic group
Maternal BMI (before pregnancy)
<21
kg/m2
21-24
25+
Maternal smoking during pregnancy
Gender
Gestational age
18
Table 1 (continued)
Birth order
first
203
61.3
other
128
38.7
yes (12 mg/dl)
209
63.1
no ( 8 mg/dl)
122
36.9
35
10.6
49-50.9
97
29.3
51-52.9
108
32.6
53-54-9
70
21.2
55+
21
6.3
34
10.2
2750-2999
41
12.4
3000-3249
72
21.8
3250-3499
76
23.0
3500-3749
61
18.4
3750+
47
14.2
Jaundice
Length
<49
cm
Birth weight
<2750
gr
19
Table 2: Mean values (M) and Standard Error (SE) of perinatal characteristics and selected compounds of the IGF-system by gender of the newborn and presence of jaundice
Gender
Boys
8
Bilirubin (in mg/dl)
Girls
12
8
p-
Total
12
value*
Characteristic
M
(SE)
M
(SE)
8
p-
12
p-
value*
M
(SE)
M
(SE)
value*
M
(SE)
M
(SE)
Maternal age
(year)
26.8
(0.79)
27.8
(0.76)
0.37
28.5
(1.12)
28.5
(0.61)
0.96
27.9
(0.77)
28.1
(0.52)
0.85
Maternal BMI
(kg/m2)
23.2
(0.64)
22.9
(0.37)
0.75
22.3
(0.41)
23.4
(0.40)
0.05
22.6
(0.35)
23.1
(0.27)
0.25
Length
(cm)
52.5
(0.28)
51.2
(0.21)
0.002
51.2
(0.23)
50.4
(0.25)
0.02
51.7
(0.18)
50.9
(0.16)
0.003
Birth weight
(gr)
3495
(63.1)
3371
(39.2)
0.10
3230
(48.0)
3176
(37.2)
0.38
3325
(39.7)
3295
(28.6)
0.52
Total blood proteins
(g/dl)
6.36
(0.10)
5.91
(0.05)
0.0001
6.36
(0.08)
5.95
(0.06)
0.0001
6.36
(0.06)
5.93
(0.04)
0.0001
IGF-I
(ng/ml)
27.45
(2.06)
22.99
(0.89)
0.05
30.07
(1.50)
25.45
(1.15)
0.01
29.13
(1.22)
23.96
(0.71)
0.0003
IGF-II
(ng/ml)
491.7
(13.48)
436.9
(9.06)
0.001
500.9
(11.57)
437.2
(11.52)
0.0001
497.6
(8.83)
437.0
(7.11)
0.0001
IGF-BP3
(μg/ml)
0.81
(0.05)
0.70
(0.04)
0.10
0.98
(0.08)
0.76
(0.07)
0.03
0.92
(0.05)
0.72
(0.04)
0.002
*:p-value derived from t-test, contrasting mean values of the indicated characteristic between newborns with and without jaundice, within sex group and in total
20
Table 3: Multiple regression-derived mutually adjusted, changes of birth length and weight by specified changes in a
series of maternal and newborn characteristics
Variable
Category or
increment
length
b
Maternal age
<25
years
25-34
0.46
birth weight
95% CI
-0.12
1.05
p-value
b
0.12
-70.4
baseline
95% CI
p-value
-157.8
17.1
0.12
baseline
35+
-0.59
-1.33
0.15
0.12
111.3
-0.37
222.9
0.05
Maternal education
3 years
0.18
-0.06
0.43
0.14
-18.0
-54.9
18.9
0.34
Ethnic group
Greek or E.U.
Maternal BMI
baseline
baseline
migrants
0.15
-0.36
0.67
0.55
30.6
-46.3
107.5
0.44
4 (kg/m2) more
0.25
-0.08
0.57
0.13
75.6
26.9
124.2
0.003
-259.2
-76.5
0.004
(before regnancy)
Maternal smoking
no
baseline
during pregnancy
yes
-0.31
Gender
female
baseline
-0.92
0.30
0.31
baseline
-167.8
baseline
male
0.90
0.41
1.40
0.0004
121.5
46.1
197.0
0.002
Gestational age
1 week more
0.25
0.03
0.47
0.03
85.4
52.1
118.7
0.0001
Birth order
first
baseline
other
0.13
-0.39
0.66
0.62
-93.2
-172.4
-13.9
0.02
Total blood proteins
1 (g/dl) more
0.24
-0.15
0.63
0.23
-16.4
-74.8
89.1
0.58
Jaundice
yes
baseline
no
0.80
Length
1 cm
IGF-I
1 standard
baseline
baseline
0.25
1.35
---
0.004
5.2
-78.6
89.1
0.90
---
88.8
72.3
105.3
0.0001
0.14
-0.12
0.41
0.29
46.4
6.6
86.2
0.02
0.03
-0.23
0.30
0.81
19.9
-19.8
59.6
0.32
0.009
-0.25
0.27
0.94
-27.0
-65.5
11.5
0.17
deviation
IGF-II
1 standard
deviation
IGF BP-3
1 standard
deviation
21
22