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Journal of the association of physicians of india • june 2013 • VOL. 61
Original Article
Cord Blood Levels of Insulin and Glucose in Full Term
Pregnancies
Anagha Sahasrabuddhe*, Shailesh Pitale**, Dhananjay Raje***, MM Sagdeo*****
Abstract
Objectives: This pilot study was undertaken to know the normal values of cord blood insulin and glucose levels
in full term normal pregnancies and pregnancies complicated with maternal conditions like pregnancy induced
hypertension (PIH), thyroid dysfunction and Gestational Diabetes Mellitus (GDM).
Method: Full term pregnancies from Ketkar maternity hospital, Nagpur, since January 2011 were included in the
study. A total of 121 cases have been studied. Demographic and clinical data of the included cases was obtained
from the hospital records. Cord blood sample was analyzed for serum insulin and plasma glucose levels. These two
metabolic parameters were used to derive (Homeostatic Model Assessment) HOMA index for insulin resistance
and Glucose-to-Insulin Ratio (GIR). The data on physical and metabolic parameters was analyzed using parametric
statistical significance tests for means and correlation using R-package
Result: The difference in glucose concentration was found insignificant (p > 0.05) across complicated and
uncomplicated pregnancies. However, for the comparison ‘no complications’ vs PIH, the insulin levels differed
significantly at 10% (p = 0.09). Accordingly, for the same comparison, GIR also indicated significant difference
at 10% (p = 0.07) between the two maternal groups. The mean cord blood glucose level was higher in PIH cases
compared to un-complicated maternal cases; while the mean insulin level was lower in PIH cases as compared to
non-complicated cases, as a result mean GIR was higher in PIH category. HOMA did not show significant difference
in any comparison. The relationship of metabolic parameters and the derived variables with birth weight in the
two maternal groups showed insignificant relationships between birth weight and dependent variables (p > 0.05).
Conclusion: The levels of insulin and glucose in normal full term pregnancies was found to be 6.75 ± 2.96 mIU/
ml and 91.69± 27.05 mg/dl respectively with GIR of 13.57±7.47 and HOMA 1.57± 0.83. Low serum insulin levels
with normal or high GIR was noted in pregnancies complicated by PIH. Insulin resistance as measured by HOMA
IR is increased in patients with hypothyroidism. Hyperinsulinemia is seen in babies with birth weight less than
2.5 kg or more than 3.5 kg.
S
Introduction
ize at birth and early growth rates are important predictors
of development of obesity and other cardiovascular risk
factors including insulin resistance later in life. Neonatal size
and body composition are influenced by parental size, maternal
food intake, physical activity and circulating concentrations
of nutrients and metabolites (folate, glucose, triglycerides,
cholesterol etc.). For a given BMI, Indians have a higher
percentage of body fat and more visceral fat than members of
other populations. This thin-fat phenotype is present at birth.1
Data regarding cord blood levels of insulin and glucose
which represent exposure of fetus to various maternal conditions
in utero is inadequate. Intrauterine growth restriction has an
adaptive hormonal profile characterized by decreased levels
of insulin and alteration in other factors like IGF (Insulin like
growth factor)-1, IGF-2, IGFBP (Insulin like growth factor
binding protein) -2, IGFBP-3 and altered IGFBP-1 and 2.2 Avon
Longitudinal Study of Pregnancy and Childhood (ALSPAC) has
*
Assistant Professor, Department of Physiology, NKP Salve Institute of
Medical Sciences, Nagpur, Maharashtra; **Consultant Endocrinologist,
Pitale Diabetes and Hormone Center, Nagpur, Maharashtra;
***
Head, Data Analysis Group, MDS Bio-Analytics Pvt. Ltd. Nagpur,
Maharashtra,; ****Professor and Head, Department of Physiology, NKP
Salve Institute of Medical Sciences, Nagpur, Maharashtra
Received: 19.07.2011; Revised: 21.09.2011; Accepted: 08.11.2011
378
shown that fetal growth is influenced by both fetal genes and
maternal-uterine-placental factors. Important maternal factors
include parity, smoking, weight gain, maternal complications
and also maternal genetic factors in the mother or fetal placenta.
The fetal gene effects are more evident in the absence of maternal
uterine growth restraint. At birth, significant gene-environment
interactions are seen. Rapid catch up early post-natal weight
gain follows maternal uterine growth restraint and strongly
predicts later childhood obesity and insulin resistance. Genetic
factors that influence early growth may have conferred some
early survival advantage in human history during times of
under nutrition. With abundant nutrition and rising obesity
rates these genetic factors and their interactions with maternal
and childhood environmental factors that influence childhood
growth may now contribute to early development of adult
disease risk. Their recognition may help development of targeted
early interventions to prevent progression towards adult
disease.3 The effect of exposure of fetus to maternal stressful
conditions like thyroid dysfunction, gestational DM, PIH on
levels of insulin and glucose needs to be explored in detail. This
study is ongoing and was undertaken with the following aims:
a. To know cord blood levels of insulin, glucose and insulin
resistance in full term normal pregnancies,
b. To study the effect of maternal conditions like pregnancy
induced hypertension (PIH), thyroid dysfunction and GDM
on levels on these parameters
© JAPI • june 2013 • VOL. 61
19
Journal of the association of physicians of india • june 2013 • VOL. 61 Table 1 : Descriptive statistics for age of mother and infant birth weight according to maternal characteristics
Maternal characteristics
No complications
Complications
Type of complication
Hypothyroidism
PIH
GDM
No of cases
89
10
15
3
Table 2: Metabolic parameters from cord blood classified
according to maternal characteristics
Results
The cases i.e., pregnant mothers, included in the study had
either no complications or complications like Hypothyroidism,
PIH and GDM. These two maternal categories were considered
in the downstream analysis. The distribution of cases along
with their mean age is shown in Table 1. The table also shows
infant’s birth weight (BW) summarized according to maternal
characteristics. The difference in the mean birth weight between
the two maternal groups was found insignificant (p > 0.05).
In view of the study aims, GIR and HOMA insulin resistance
derived from the two metabolic parameters, glucose and insulin,
were referred as primary indicators of fetal insulin sensitivity.
As regards the frequency distribution of these metabolic
parameters, both indicated positive skewness, as a result the
derived variables (GIR and HOMA) also indicated positive
skewness. Since the statistical parametric tests are based on the
assumption of normality of data, each data set (glucose, insulin,
GIR and HOMA) on original scale was log-transformed. The
mean and standard deviation for each data set was obtained
according to maternal characteristics and shown in Table 2. The
geometric mean on original scale (equivalent to arithmetic mean
of log-transformed data) for each variable was obtained as a
measure of central tendency. The pseudo-standard deviation was
obtained for each variable on the original scale. The significance
of difference for metabolic parameters and the derived variables
was obtained between two maternal groups using t-test for
independent samples. Also, the significance was tested between
mothers with no complications and those with PIH (n1=15), as
well as between no complications and those with Hypothyroidism
(n2=10). The equality of variance across groups was ascertained
by Levene’s test. The results are shown in Table 2. The difference
in glucose concentration was found insignificant (p > 0.05)
across both the comparisons. This result corroborated with
the finding in some similar study.4 The difference in the mean
insulin level between the two maternal groups was insignificant.
However, for the comparison no complications – PIH, insulin
levels differed significantly at 10% (p = 0.09). Accordingly, for
the same comparison, GIR also indicated significant difference
at 10% (p = 0.07) between the two maternal groups. The mean
cord blood glucose level was higher in PIH cases compared to
non-complicated maternal cases; while the mean insulin level
was smaller in PIH cases as compared to non-complicated cases,
as a result mean GIR was higher in PIH category. The GIR in
other comparisons was found insignificant. HOMA also did not
show significant difference in any comparison.
* p < 0.1
To correlate insulin resistance with birth weight.
Methods
In this pilot study, full term pregnancies from Ketkar
Maternity hospital, Nagpur since January 2011 were studied. The
inclusion criterion was – full term delivery; while the exclusion
criterion was – premature delivery. Only those patients who
signed the informed consent were recruited in the study. A total
of 121 cases have been included in the study. A detailed history of
each included case was recorded in a structured format. Height
was measured on wall mounted stadiometer and weight was
measured by calibrated Tainita scale. Birth weight and height
of the newborn was obtained from the medical records. Data
on ANC complications was also obtained from the history and
review of medical records. Cord blood sample was analyzed
for the two metabolic parameters - serum insulin and plasma
glucose. Serum insulin was measured by radioimmunoassay
using Diasorin kit. Plasma glucose level was estimated by
GOD-POD method. The study was approved by the independent
ethics committee, Nagpur.
Statistical Methods
The two metabolic parameters were used to derive HOMA
index for insulin resistance and Glucose-to-Insulin Ratio (GIR).
The significance of difference of these metabolic parameters
between mothers with complication and without complications was
analyzed using parametric statistical significance test (t-test).
© JAPI • june 2013 • VOL. 61 Mean birth weight (kg)
2.82±0.48
2.79± 0.64
2.74± 0.37
3.26± 1.1
Also, correlation and its significance between the birth weight
and each metabolic parameter as well as the above two derived
parameters were studied using Pearson’s correlation coefficient.
All the analysis was performed using R programming language.
Cord blood metabolic
Maternal characteristic
parameter
No complications
Complications
Glucose (mg/dl)
91.69 ± 27.057
All complications: 92.70
± 42.47
[PIH: 96.33 ± 30.94 ;
Hypothyroidism: 93.41 ±
60.41; GDM: 68.61 ± 60.9;
IUGR: 98.76 ± 44.14]
Insulin (mU/ml)
6.75 ± 2.96
All complications: 6.12 ±
3.113
[PIH: 5.64 ± 2.038 ;
Hypothyroidism: 6.87 ±
4.18 ; GDM: 6.16 ± 1.92;
IUGR: 6.223±2.50]
Glucose-to-insulin
13.57 ± 7.47
All complications: 14.79
ratio
± 12.99
[PIH: 17.076 ± 11.41* ;
Hypothyroidism: 13.57 ±
10.39; GDM: 11.13±19.66 ;
IUGR: 15.85± 16.1]
HOMA
1.572 ± 0.837
All comparisons: 1.442 ±
0.207
[PIH: 1.38 ± 0.475;
Hypothyroidism: 1.631 ±
1.22; GDM: 1.073±0.404;
IUGR:1.56 ± 0.448 ]
c.
Mean age of mother (yr)
28.12±3.2
27.4± 3.2
28.66± 4
31± 2
Analysis of the relationship of metabolic parameters and the
derived variables with birth weight in the two maternal groups
was also done. A correlation of each dependent variable with
birth weight was obtained using Pearson’s correlation coefficient.
Figure 1 provides scatter plots of birth weight and four dependent
379
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Journal of the association of physicians of india • june 2013 • VOL. 61
Fig. 1 : Scatter plots showing relatedness of metabolic parameters
and derived parameters with birth weight in case of pregnancies
with no complications
Fig. 2 : Scatter plots showing relatedness of metabolic parameters
and derived parameters with birth weight in case of pregnancies
with complications
variables along with the respective correlation coefficient and
significance values for mothers with no complications. The data
shows insignificant relationships between birth weight and all
dependent variables (p > 0.05). Similar analysis was performed
for mothers with Complications and the results are shown in
Figure 2. In this group, cord blood glucose level was lower in
low weight babies and higher in heavy weight babies, thereby
leading to a significant positive correlation of 0.31 (p = 0.04).
Contrary to this, the insulin levels were on higher side in low
weight babies and lower in heavy weight babies, as evident
through correlation plot of birth weight and insulin. As a result,
GIR showed significant positive correlation of 0.32 (p = 0.03)
with birth weight. HOMA did not show any relationship with
birth weight. Hyperinsulinemia, defined as insulin levels greater
than nineteen,5 was observed in 4 out of 121 (3.3%) samples. In
all cases of hyperinsulinemia birth weight was either low (< 2.5
kg) in 3 cases or more (> 3 kg) in one case. Overall incidence of
low birth weight was more in complicated pregnancies 31.25%
as against 20% in uncomplicated pregnancies. Our results
showed HOMA insulin resistance was greater than 2.5 in 18%
of the cases. Eighteen of them were normal pregnancies. Thirty
percent of the fetuses born to hypothyroid mothers had HOMA
insulin resistance greater than 2.5 and cord sample of one (out
of 16) PIH patient had HOMA greater than 2.5.
the benefit of the brain but at the expense of glucose transport
into the muscles and muscle growth.7 The thinness of Indian
babies is due to poor muscle and small abdominal viscera.
The small Indian babies are programmed to deposit more fat
from their intrauterine life. Exaggeration of this tendency in
later life is associated with insulin resistance syndrome.8 Low
birth weight has been linked to visceral adipose tissue (VAT)
accumulation, insulin resistance and cardiovascular risk factors
in middle aged and elderly individuals, many of whom may be
classified as metabolically obese normal weight with metabolic
syndrome.9 It has been suggested that increased activity of the
hypothalamic-pituitary-adrenal axis may link low birth weight
with subsequent development of cardiovascular risk factors and
disease.10 It is imperative to recognize that insulin resistance
becomes apparent during infancy, probably because of IUGR
in pregnancy and catch up growth in early infancy result in
metabolic programming leading to higher risk of various
components of metabolic syndrome in adult life. Increasing
evidence links maternal malnutrition, low birth weight and
nutritional programming in early life with the development of
constellation of metabolic syndrome in adult life, with common
denominator of insulin resistance.11
Discussion
Human beings are plastic and able to adapt to their
environment. During development, the organs and systems of
the body go through critical periods when they are plastic and
sensitive to the intrauterine environment. It enables production
of phenotypes that are better matched to their environment than
would be possible if the same type of phenotype was produced
in all environments. Developmental plasticity is defined as the
phenomenon by which one genotype can give rise to a range
of different physiological or morphological states to different
environmental conditions during development6. The fetus
responds to harsh intrauterine environment by adaptations
like reduced body size and altered metabolism, which help it
to survive shortage of food after birth.7
An undernourished baby may establish a thrifty way of
handling food. Insulin resistance, which is associated with low
birth weight, may be viewed as persistence of fetal response
by which blood glucose concentrations were maintained for
380
For better understanding of the pathophysiology of the
process, it is necessary to generate a normative data of the
insulin and glucose levels and establish cut off value of insulin
resistance at birth. Fetal insulin concentrations reflect the
intrauterine glucose load given to the fetus by the mother.12 In
fetus, blood glucose levels are determined by placenta- the fetal
levels reflecting maternal levels with no endogenous glucose
production.
This is a pilot study and so far we have included 121 full
term pregnancies. Of these, 89 were normal uncomplicated
pregnancies, 10 with antenatal maternal hypothyroidism, 15 had
pregnancy induced hypertension, 3 with Gestational diabetes.
Low birth weight (< 2.5 kg) was seen in 25 newborns and birth
weight more than 3.5 kg was noted in 6 babies, of which 2 had
GDM.
The levels of insulin and glucose in normal full term
pregnancies was found to be 6.75 ± 2.96 mIU/ml and 91.69±
27.05 mg/dl respectively with GIR of 13.57±7.47 and HOMA 1.57±
0.83. Glucose level was lower in low weight babies and higher
in heavy weight babies, while insulin levels were on higher
side in low weight babies and lower in heavy weight babies
© JAPI • june 2013 • VOL. 61
Journal of the association of physicians of india • june 2013 • VOL. 61 metabolic changes.16 In our study too, we found higher levels of
glucose as compared with the normal. Comparatively, insulin
levels were lower which again speaks of immaturity of fetal
beta cells in handling glucose. Although it remains uncertain
as to what extent these factors are pathogenic in hypertensive
pregnancy, the available data suggests that some may play a
role in disease evolution, whereas others may be markers of
the underlying disease process. Exaggerated hyperinsulinemia
relative to normal pregnancy is well described in women with
established preeclampsia.16,17
and consequently GIR showed positive correlation with birth
weight in complicated pregnancies. It can be hypothesized that
harsh intrauterine conditions in complicated pregnancies could
alter the fetal programming and may affect development and
functioning of beta cells. Higher incidence of low birth weight in
complicated pregnancies reflects effect of such complications on
fetal development. Significantly lower insulin levels (5.25±2.81)
and higher insulin sensitivity (11.02±1.85) was seen in some
other studies done on IUGR newborns.13,14 Both the studies
reported higher TSH levels. Insulin sensitivity was noted to
have negative association with T4 and positive association with
TSH and concluded that thyroid hormones may play a role in
increased insulin sensitivity at birth in IUGR.13 It is postulated
that decrease in growth hormone might be the pathogenesis of
IUGR. The decreased GH and insulin might compromise the
basic metabolism of the fetus.14 The change of early hypothyrosis
of fetus with IUGR might benefit them to live in unfavorable
environment.14 Our study reports no difference in TSH levels of
normal, IUGR and low birth weight babies. Thus, our finding is
contradictory to both these studies.
Increased oxidative stress has been reported in fetuses born to
mothers with established PIH. Also there is a report of decreased
antioxidant protective mechanism in such babies18. Whether
this stress has any impact on developing beta cells of the fetus
is unknown but possibility cannot be ruled out.
Singleton infants with intrauterine growth restriction have
an adaptive hormonal profile characterized by decreased levels
of insulin like growth factor IGF-1, IGF-2, insulin like growth
factor binding protein-3(IGFBP-3) and insulin according to one
more study.3,18,19
Higher levels of cord blood insulin are reported in mothers
with impaired glucose tolerance. Small for gestational age
(SGA) babies have poor ketogenic responses and enhanced
glycolysis. In addition, insulin secretion may be inappropriately
high and not suppressed by blood sugar levels in them. Both,
Type 2 diabetes and low birth weight are common in India. To
determine whether low birth weight is associated with reduced
glucose tolerance in Indian children, glucose tolerance tests were
carried out on 379 four year old children in Pune, India. Among
201 children who were followed for the routine postnatal wards
at birth, those with lower birth weights had higher plasma
glucose and insulin concentrations, thirty minutes after an oral
glucose load, independently of their current size (p = 0.01 and
0.04, respectively). Mean glucose and insulin concentrations
were 8.1 mmol/ l-1 and 321 pmol/ l-1 in children whose birth
weight had been 2.4 kg or less, compared with 7.5 mmol/ l-1 and
289 pmol/ l-1 in those who weighed more than 3.0 kg. Among
178 children who were observed in the Special Care Baby Unit,
those with lower birth weights also had higher plasma insulin
concentrations at thirty minutes but there were no trends with
plasma glucose. The findings suggest that Indian children with
reduced intra-uterine growth have reduced glucose homeostasis
after a glucose challenge. This is consistent with the hypothesis
that Type 2 diabetes mellitus in India may be programmed in
fetal life.15
Size at birth and early postnatal growth rates are important
determinants of human perinatal survival. They also predict
the tempo of growth, adult height and long term risks of
obesity, type-2 DM and cardiovascular disease. Results of
Avon Longitudinal Study of Pregnancy and Childhood
(ALSPAC) show that fetal growth is influenced by both fetal
genes and maternal-uterine-placental factors. With abundant
nutrition and rising obesity rates, these genetic factors and their
interactions with maternal and childhood environmental factors
that influence childhood growth may contribute to the early
development of adult disease risk.20
Results of our study match with findings of a few other
studies which show no evidence of increased metabolic risk at
birth.2,21 Studies have reported high insulin levels in macrosomic
infants than controls (with normal birth weights) but glucose
levels did not differ in both groups.22
Comparative studies indicate that metabolic responses to
obesity may be greater in South and East Asians than their
Western counterparts at given Body mass Indexes (BMIs).
Higher percentage of body fat in Asians at given BMIs and over
responsiveness to obesity may in part explain the phenomenon
for which the underlying causes are not clear.11 Low birth weight
is at least partly responsible for hyperactivity of hypothalamic
– pituitary- adrenal axis, which leads to a state of functional
hypercortisolism with increased circulating cortisol levels and
greater responsiveness of the hypothalamic – pituitary- adrenal
axis which might play a role in development of metabolic
syndrome at both central and peripheral level later in life.23
Our preliminary data shows significant correlation of cord
blood glucose and GIR with birth weight, in pregnancies with
complications like maternal hypothyroidism, IUGR and PIH.
Long term longitudinal studies are required to know as to
how intrauterine conditions lead to permanent changes in fetal
programming and plasticity.
Since there is no data available on cord blood normal GIR as
well as HOMA resistance, the findings of various groups have
been compared with the levels of normal full term pregnancies
in our study.
Hyperinsulinemia was observed in 4 out of 121 pregnancies.
In three of these four cases, birth weight was not normal. Three
had low birth weight (< 2.5 kg), while the fourth had more than
3.5 kg. A very high insulin level (40 mIU/ml) was seen in one of
the four IUGR newborns. This high level in IUGR could be the
result of immaturity of the beta cells, which is well documented
in literature. Immaturity of normal homeostatic mechanisms
may therefore result in hypoglycaemia in IUGR and SGA babies.
Whether hyperinsulinemia is a result of insulin resistance in
high birth weight is not known. However our study reports
significant low levels of insulin in PIH as compared with normal
resulting in high Glucose- Insulin Ratio (p < 0.1). In women
whose pregnancies are complicated due to hypertension, there
appears to be an exaggeration of insulin resistance and associated
© JAPI • june 2013 • VOL. 61 21
Conclusion
In our pilot study, levels of insulin and glucose in normal
full term pregnancies was found to be 6.75 ± 2.96 mIU/ml and
91.69± 27.05 mg/dl respectively with GIR of 13.57±7.47 and
HOMA 1.57± 0.83.
Low serum insulin levels with normal or high GIR was
noted in pregnancies complicated by PIH. Insulin resistance
381
22
Journal of the association of physicians of india • june 2013 • VOL. 61
as measured by HOMA IR is increased in patients with
hypothyroidism.
11. Tabish SA. Metabolic Syndrome: A growing clinical challenge.
Indian J of Endocrinol and Metab 2008;12:11-14.
Hyperinsulinemia is seen in babies with birth weight less
than 2.5 kg or more than 3.5 kg.
12. Leipold H, Kautzky-Willer A, Ozbal A, Bancher-Todesca D, Worda
C. Fetal hyperinsulinism and maternal one hour post load plasma
glucose level. Obstet Gyneacol 2004;104:1301-1306.
Acknowledgements
13. Setia S, Sridhar M G, Koner B C, Bobby Z, Bhat V, Chaturvedula
L. Increased insulin sensitivity in intrauterine growth retarded
newborns - Do thyroid hormones play a role? Clin Chem Acta
2007;376:37-40.
The authors would like to thank Dr. Mangala Ketkar, Ketkar
Hospital, Nagpur for providing access to hospital records for
this study.
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