BIOCHEMICAL PARAMETER VARIATIONS IN INFANTS
OF DIABETIC MOTHERS
Dr.M.Padma Geethanjali1 ,Dr.V.Seetha Rama Raju2, Dr.P.Satyanarayana Raju2
1 Professor, Physiology, Andhra Medical College,Visakhapatnam, A.P, India.
2 Assistant professor, Physiology, Andhra Medical College,Visakhapatnam, A.P,India.
ABSTRACT
This study was carried on 40 neonates their gestational age ranged from 32-41weeks. Their mothers have
diabetes mellitus have both pregestational (including type I and type II diabetes) and gestational diabetes
admitted to Neonatal Intensive Care Unit (NICU) with apparent clinical complications due to maternal
diabetes. They were collected from NICU of King George Hospital. 20 healthy neonates of the same gestational
age and the same socioeconomic standards their mothers had no diabetes or other diseases were taken as a
control group.*Neonates have been divided into the following 3 groups:-Group I: Control group. (n=20),Group
II: IDMs (Infants of Diabetic Mothers) whose mothers had pre-gestational Diabetes (n=20), Group III:
IDMs whose mothers had gestational diabetes mellitus. (n=20).A full history was taken and thorough clinical
examination for all neonates was performed. The following parameters were assessed: 1- Serum glucose level.
2- Serum calcium level.3.Serum bilirubin level. All samples were taken on first day of admission (patients are
referred to as Group IIa for IDM whose mothers had pregestational diabetes and Group IIIa for patients whose
mothers had gestational diabetes mellitus) and before discharge from NICU for IDMs (patients are referred to
as Group IIb for IDM whose mothers had pregestational diabetes and Group IIIb for patients whose mothers
had gestational diabetes mellitus). For control group we assessed the parameters once on first day of life just
afterbirth. Measurements were obtained through automated systems. We measured Serum glucose, calcium,
bilirubin by Mindray semi auto analyser. In conclusion our results indicate that some of the biochemical changes
in IDMs (calcium and glucose) were improved with admission while for bilirubin the rise persists within the
same group. On the other hand when compared to control, the reversibility in hypocalcaemia and
hyperbilirubinemia tend to be slower than the reversibility of hypoglycemia.
KEY WORDS: Maternal Diabetes, Biochemical, cord blood,infants.
INTRODUCTION
Diabetes mellitus during pregnancy increases fetal and maternal morbidity and mortality.
Gestational diabetes mellitus(GDM) represents approximately 90% of these cases and affects
from 2 to more than 10% of all pregnancies, and sometimes much higher, depending on the
population being tested and the diagnostic criteria used and varies in direct proportion to
type II diabetes mellitus in the background population.1
Metabolic changes occur in normal pregnancy in response to the increase in nutrient needs of
the fetus and the mother. There are two main changes that occur during pregnancy, the first is
progressive insulin resistance that begins near mid-pregnancy and progresses through the
third trimester to the level that approximates the insulin resistance seen in individuals with
type II diabetes mellitus.2 The insulin resistance appears to result from a combination of
increased maternal adiposity and the placental secretion of anti-insulin hormones.
The second change is the compensatory increase in insulin secretion by the pancreatic
beta-cells to overcome the insulin resistance of pregnancy. As a result, circulating glucose
levels are kept within normal. If there is maternal defect in insulin secretion and in glucose
utilization, GDM will occur as the diabetogenic hormones rise to their peak levels. 3
Abnormal concentrations of maternal glucose, lipids, and amino acids may influence fetal
development, leading to changes in metabolism, weight, and behavior. Congenital anomalies
are more frequent in infants of diabetic mothers. Increased glucose metabolism in embryo
cells increases oxidative stress through hexosamine biosynthetic pathway or hypoxia.4 5 Fetal
organogenesis is completed by seven week post conception and there is an increased
prevalence of congenital anomalies and spontaneous abortions in diabetic women with poor
glycaemic control during this period.
If the mother has hyperglycaemia, the fetus will be exposed to either sustained or
intermittent hyperglycaemia. Before 20 weeks’ an acute hyperglycemic stimulus in the
human fetus stimulates fetal insulin release only in diabetic pregnancy. After 20 weeks'
gestation, the fetus responds to hyperglycemia with pancreatic beta-cell hyperplasia and
increased insulin levels.6 The fetus may have cardiac arrhythmia due to decreased potassium
level with elevated insulin and glucose levels. Chronic fetal hyperglycemia and
hyperinsulinemia increase the fetal basal metabolic rate and oxygen consumption, leading to
a relative hypoxic state. The fetus increases oxygen-carrying capacity through increased
erythropoietin production, and polycythemia.
Infants born to mothers with glucose intolerance are at an increased risk of morbidity
and mortality related to the respiratory distress, growth abnormalities, hyperviscosity
secondary to polycythemia, hyperbilirubinemia, hypoglycemia, adverse neurodevelopment
outcomes, congenital anomalies, hypocalcaemia, hypomagnesaemia, and iron abnormalities,
cardiovascular malformations.7
METHODS AND MATERIALS
This study was carried on 40 neonates their gestational age ranged from 32-41weeks. Their
mothers have diabetes mellitus have both pre-gestational (including type I and type II
diabetes) and gestational diabetes admitted to Neonatal Intensive Care Unit (NICU) with
apparent clinical complications due to maternal diabetes. They were collected from
NICU of King George Hospital. 20 healthy neonates of the same gestational age and the same
socioeconomic standards their mothers had no diabetes or other diseases were taken as a
control group.
*Neonates have been divided into the following 3 groups:Group I: Control group. (n=20)
Group II: IDMs whose mothers had pre gestational diabetes (n=20)
Group III: IDMs whose mothers had gestational diabetes mellitus. (n=20)
A full history was taken and thorough clinical examination for all neonates was performed.
*The following parameters were assessed: 1- Serum glucose level. 2- Serum calcium level.
3- Serum bilirubin level.
All samples were taken on first day of admission (patients are referred to as Group IIa for
IDM whose mothers had pregestational diabetes and Group IIIa for patients whose mothers
had gestational diabetes mellitus) and before discharge from NICU for IDMs (patients are
referred to as Group IIb for IDM whose mothers had pregestational diabetes and Group
IIIb for patients whose mothers had gestational diabetes mellitus).
For control group; we assessed the parameters once on first day of life just afterbirth.
Measurements were obtained through automated systems. We measured Serum glucose,
calcium, bilirubin by Mindray semi auto analyser.
Statistical analysis: Data were statistically described in terms of, mean and standard
deviation (±SD).
-The Arithmetic Mean (x) : The mean is the sum of the observations divided by the number
of observations (Altman, 2005).
X=S(x)/n
S(x) =sum of the individual values. n = numbers of measurements.
-Standard Deviation (SD)
d2=sum of deviation of the individual values from the arithmetic mean of the series.
n-1=degree freedom (Altman, 2005).
-Comparisons:
Comparison of quantitative variables between the study groups was done using
Kruskal Wallis analysis of variance (ANOVA) test. Within group comparison of quantitative
variables was done using Wilcoxon signed rank test for paired(matched) samples.
-Probability ″P value″-- It can be estimated from the degree of freedom.
Limits of significance: P>0.050 =non-significant. P<0.050 = significant.
-All statistical calculations were done using computer programs Microsoft Excel 2007
(Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the Social Science;
SPSS Inc., Chicago, IL, USA) version 17 for Microsoft Windows XP.
RESULTS:
A-Descriptive statistics
Table (1): Shows mean ±standard deviation (SD) of the measured variables among
studied group.
Parameter
Control
Group IIa
Group IIb
Group IIIa
Group IIIb
Glucose(mg/dl)
84.25±14.414
49.95±20.493
84.25±16.049
65.45±41.140
88.15±13.816
Calcium(mg/dl) 9.80±.894
7.68±1.348
8.59±1.002
7.34±1.203
8.71±1.173
TSB(mg/dl)
2.79±1.261
9.80±5.807
7.89±4.197
5.81±3.898
6.82±4.068
DSB(mg/dl)
0.80±.433
1.42±2.857
0.74±.446
0.56±.239
0.64±.343
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
B-Comparative studies of different parameters among the studied groups
1-Comparison of quantitative variables within the same group at admission and before
discharge
-Group II (IDMs whose mothers had pregestational diabetes)As revealed from table (2):
There was a significant increase (P value < 0.05) in serum glucose level in group II before
discharge (84.25±16.049mg/dl) in comparison to values on admission (49.95±20.493mg/dl).
There was also a significant increase (P value <0.05) in serum calcium level before discharge
(8.59±1.002mg/dl) compared to level on admission (7.68±1.348mg/dl).
Table (2) Paired sample test for serum glucose and calcium at admission and before
discharge (Group II)
TABLE 2:
pairs
T
Sig.(2- tailed)
Glucose2 - Glucose1
6.551
.000*
Calcium2 - Calcium1
4.577
.000*
* P<0.05= significant
-As revealed from table (3)
In group II there was no statistically significant difference between, TSB levels before
discharge (7.89±4.197 mg/dl) to values measured on admission(9.80±5.807 mg/dl).Also there
was no significant difference in DSB measurements before discharge (0.74±.446 mg/dl)
compared to those on admission(1.42±2.857 mg/d
Table (3) Paired sample test for total and direct bilirubin at admission and before
discharge (Group II)
TABLE3:
pairs
T
Sig.(2- tailed)
TSB2-TSB1
-1.243
.229
DSB2-DSB1
-1.002
.329
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
Group III (IDMs whose mothers had gestational diabetes)
-As revealed from table (4):
There was a significant increase (P value < 0.05) in serum glucose level in group III
before discharge (88.15±13.816mg/dl)in comparison to values on admission
(65.45±41.140mg/dl). There was also a significant increase (P value <0.05) in serum calcium
level before discharge (8.71±1.173mg/dl) compared to level on admission
(7.34±1.203mg/dl).
Table (4) Paired sample test for serum glucose and calcium at admission and before
discharge (Group III).
TABLE4:
pairs
T
Sig.(2- tailed)
Glucose2 - Glucose1
2.275
.035*
Calcium2 - Calcium1
7.850
.000*
* P<0.05= significant
-As revealed from table (5)
In group III there was no statistically significant difference between, TSB levels before
discharge (6.82±4.068 mg/dl) to values measured on admission(5.81±3.898 mg/dl).Also there
was no significant difference in DSB measurements before discharge(0.64±.343 mg/dl)
compared to those on admission(0.56±.239mg/dl).
Table (5) Paired sample test for total and direct bilirubin at admission and before
discharge (Group III).
TABLE5:
pairs
T
Sig.(2- tailed)
TSB2-TSB1
.877
.392
DSB2-DSB1
.895
.382
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
2-Analysis of Variance (ANOVA) test
-Comparison between variables on admission in group II and group III and control
group:
As revealed from table (6): There was a significant decrease (P value < 0.05) in serum
glucose level on admission in both group II (49.95±20.493mg/dl) and group III
(65.45±41.140 mg/dl) compared to control group (84.25±14.414mg/dl) (Figure1).There was
also a significant decrease (P value < 0.05) in serum calcium level in both group II
(7.68±1.348 mg/dl) and group III (7.34±1.203 mg/dl) on admission compared to control
group (9.80±.894 mg/dl) (Figure 2).
Table (6) Comparison of serum glucose and calcium in group II, group III on admission
and control group.
Measured variable
Control (n=20)
Group IIa(n=20)
Group IIIa(n=20)
P value
Glucose (mg/dl)
84.25 + 14.414
49.95±20.493
65.45±41.140
0.000*
Calcium(mg/dl)
9.80 + 894
7.68±1.348
7.34±1.203
0.000*
*P<0.05= significant
As revealed from table (7):
There was a significant increase (P value < 0.05) in TSB in group II(9.80±5.807 mg/dl) and
group III on admission (5.81±3.898 mg/dl) compared to control group (2.79±1.261mg/dl)
(Figure 3).On the other hand there was no statistically significant difference between DSB
levels in group II (1.42±2.857mg/dl) and group III on admission (0.56±0.239 mg/dl)
compared to control group (0.80±0.433 mg/dl) (Figure 4).
Table (7) Comparison of total and direct serum bilirubin in group II, group III on
admission and control group.
Measured variable
Control (n=20)
Group IIa(n=20)
Group IIIa(n=20)
P value
TSB (mg/dl)
2.79 +1.261
9.80 ± 5.807
5.81 ± 3.898
0.000*
DSB(mg/dl)
0.80 + 433
1.42 ± 2.857
0.56 ± .239
0.180
<0.05= significant
Comparison between variables before discharge in group II and group III and control
group:
- As revealed from table (8):
There was no significant difference in serum glucose level in both group II
(84.25±16.049mg/dl) and group III (88.15±13.816 mg/dl) before discharge compared to
control group (84.25±14.414mg/dl) (Figure 1).
There was a significant decrease (P value < 0.05) in serum calcium level in both
group II (8.59±1.002mg/dl) and group III (8.71±1.173mg/dl) before discharge relative to
control group (9.80±.894 mg/dl) (Figure 2)
Table (8) Comparison of serum glucose and calcium in, group II, group III before
discharge and control group.
Measured
Control
Group II b
Parameter
(n=20)
(n=20)
Group
(n=20)
Glucose(mg/dl)
84.25+ 14.414
84.25 + 16.049
88.15 + 13.816
0.644
Calcium(mg/dl)
9.80±.894
8.59 + 1.002
8.71 + 1.173
0.005*
III
b
P - value
*P<0.05= significant
-As revealed from table (9):
There was a significant increase (P value < 0.05) in TSB in group II(7.89±4.197mg/dl) and
group III (6.82±4.068mg/dl) before discharge compared to control group (2.79±1.261mg/dl)
(Figure 3).On the other hand there was no statistically significant difference between DSB
levels in group II (0.74±.446mg/dl) and group III (0.64±.343 mg/dl) before discharge
compared to control group (0.80±.433 mg/dl) (Figure 4).
Table (9) Comparison of total and direct serum bilirubin in group II, group III before
discharge and control group.
Group II b
Measured Parameter
Control (n=20)
Group III b (n=20) P - value
(n=20)
TSB(mg/dl)
2.79 + 1.261
7.89 + 4.197
6.82 + 4.068
0.000*
DSB(mg/dl)
0.80 + .433
0.74 + .446
0.64 + .343
0.451
*P<0.05= significant
DISCUSSION:
The presence of diabetes before pregnancy is well known to be a risk factor for adverse
neonatal outcomes, including increased rates of perinatal mortality, congenital anomaly, and
macrosomia. In 1989, the St. Vincent Declaration in Europe made it a healthcare goal to
improve outcomes of diabetic pregnancies such that the incidence of adverse outcomes
approached those of the general population. Since 1989, care of diabetes in general and
during pregnancy has changed; however, population-based studies show that the goals of the
St. Vincent Declaration have not been reached.8
In the present study, serum glucose level significantly increased in the same group
before discharge than on admission; in group II (84.25±16.049mg/dl before discharge and
49.95±20.493 mg/dl on admission), and group III (88.15±13.816 mg/dl before discharge and
65.45±41.140 mg/dl on admission). Serum glucose level was significantly decreased in group
II and group III on admission as compared to control group (84.25±14.414 mg/dl) (table 6),
with no significant difference between serum glucose in group II and group III before
discharge and control group (table 8).
The alterations in maternal metabolism resulting from diabetes mellitus causes excess
provision of maternal metabolic fuels to the fetus, resulting in pancreatic beta-cell
hypertrophy, hyperplasia, fetal and neonatal hyperinsulinism. Hypoglycaemia is more likely
to occur in macrocosmic IDMs because hyperinsulinism is responsible for both fetal
overgrowth and hypoglycemia. Several studies also suggest that these IDM may fail to
release glucagon or catecholamine in response to hypoglycaemia; these hormonal alterations
result in both increased glucose clearance and diminished glucose production.
Glucose production rates vary from attenuated to normal, likely, reflecting
differences in maternal glycemic control. The Hyperglycemia and Adverse Pregnancy
Outcome (HAPO) study of around 25,000 non-diabetic pregnancies revealed strong
associations between glucose values and increased fetal size and hyperinsulinemia at birth findings adding strong support to the maternal hyperglycemia - fetal hyperinsulinism theory.
Mothers with the highest fasting glucose had infants with the highest frequency of clinical
neonatal hypoglycaemia.9
Vela-Huerta et al.,(2008).10 concluded that insulin levels and insulin resistance were
significantly higher in IDMs. The trend of higher leptin levels in IDMs than infants of non
diabetic mothers (INDMs) shows that leptin could be related to insulin resistance in these
infants. This is in agreement with Westgate et al., (2006).11 who demonstrated raised cord
insulin and leptin. Concentrations in offspring of mothers with type 2 diabetes and GDM.
Maayan-Metzgeret al.,(2009)12 demonstrated that IDMs tend to have a high rate of
hypoglycemia on the first day of life when a relatively high cut-off point (47 mg/dl) is used,
and should be closely monitored. With presumably tighter control of gestational diabetes, the
risk of symptomatic hypoglycemia appears diminished. If glucose monitoring of
asymptomatic newborns is to be performed, it needs only be done in the first 2hours of life.13
In the current study serum calcium levels were significantly increased in the same group
before discharge than on admission in group II (8.59±1.002mg/dl before discharge and
7.68±1.348 mg/dl on admission), and group III (8.71±1.173 mg/dl before discharge and
7.34±1.203 mg/dl on admission). Serum calcium level was significantly decreased in group II
and group III on admission as well as before discharge as compared to control
group(9.80±.894 mg/dl) (table 6,8). Hypocalcaemia is a common problem among IDMs
during the neonatal period. This usually occurs in association with hyperphosphatemia and
occasionally with hypomagnesemia. 14
Banerjee et al. (2003).15 suggested a possible mechanism for hypocalcaemia in infants of
diabetic mothers; poor diabetic control leads to glycosuria and consequent increased urinary
loss of magnesium and therefore a low maternal blood magnesium concentration,
consequently maternal hypomagnesaemia leads to fetal hypomagnesaemia. The paradoxical
block of PTH release under magnesium deficiency seems to be mediated through a
mechanism involving an increase in the activity of G α subunits of heterotrimeric G-proteins
with consequent hypoparathyroidism, causing neonatal hypocalcaemia. Moreover, IDMs
exhibit hypomagnesemia and hypocalcemia, urinary excretion of calcium and magnesium is
reduced. The basis for reduced excretion of calcium and magnesium involves increased
tubular transport activity and possibly increased sensitivity of these mechanisms to PTH.
Parathormone concentrations are significantly lower in IDM during the first 4 days of
life. This may be a result of hypomagnesaemia, which limits parathormone secretion even in
the presence of hypocalcaemia; high incidence of birth asphyxia and prematurity in infants of
diabetic mothers are also contributing factors. Asphyxia is associated with delayed
introduction of feeds, increased calcitonin production, increased endogenous phosphate load,
and alkali therapy all may contribute to hypocalcemia. In prematurity there is poor intake,
decreased responsiveness to vitamin D, increased calcitonin, hypoalbuminemia leading to
decreased total but normal ionized calcium. Also, there may be diminished end-organ
responsiveness to hormonal regulation of mineral homeostasis, although the functional
capacity of the gut and kidney improves rapidly within days after birth .
In the present work, there was no significant difference between TSB or DSB within the
same group before discharge compared to level on admission; in group II (TSB was
7.89±4.197 mg/dl before discharge and 9.80±5.807 mg/dl on admission; DSB was 0.74±.446
mg/dl before discharge and 1.42±2.857mg/dl on admission) and group III (TSB was
6.82±4.068 mg/dl before discharge and 5.81±3.898 mg/dl on admission; DSB was 0.64±.343
mg/dl before discharge and 0.56±.239 mg/dl on admission).
TSB was higher in IDMs from PGDM than IDMs from GDM (table 1). There was a
significant increase in TSB in group II and group III both on admission and before discharge
compared to control group (2.79±1.261mg/dl) (table 7,9) .
There was no significant difference in DSB between group II and group III neither on
admission nor before discharge and the control group (0.80±.433 mg/dl), as shown in (table7,
9,). At any time in the infant's first few days after birth, the serum bilirubin level reflects a
combination of the effects of bilirubin production, conjugation, and entero hepatic
circulation. An imbalance between bilirubin production and conjugation is fundamental in the
pathogenesis of neonatal hyper bilirubinemia.16
Deficient UGT1A1 activity, with impairment of bilirubin conjugation, has long been
considered a major cause of physiologic jaundice. In human infants, the early postnatal
increase in serum bilirubin appears to play an important role in the initiation of bilirubin
conjugation. In contrast to the current study Jaber, (2006).17 found that total bilirubin was
significantly elevated in GDM group compared to PGDM group, with total bilirubin
levels higher than reference range in all groups of IDM.
The rate of prematurity in infants of diabetic mothers is five times that of the general
population. Hyperbilirubinemia in preterm infants is more prevalent, more severe, and its
course more protracted than in term neonates, as a result of exaggerated neonatal red cell,
hepatic, and gastrointestinal immaturity. The postnatal maturation of hepatic bilirubin uptake
and conjugation may also be slower in premature infants. In addition, a delay in the initiation
of enteral feedings so common in the clinical management of sick premature newborns may
limit intestinal flow and bacterial colonization resulting in further enhancement of bilirubin
enterohepatic circulation. Ligandin, the predominant bilirubin-binding protein in the human
liver cell, is deficient in the liver of newborn monkeys. It reaches adult levels in the monkey
by 5 days of age, coinciding with a fall in bilirubin levels.
CONCLUSION:
For all subjects, serum glucose level, serum calcium level, total serum bilirubin, direct serum
bilirubin complete blood count was investigated. For control group; measurements were
performed once just after birth while for IDMs (both group II and III), measurements were
performed twice; on admission to NICU and before discharge.
Results were statistically analysed and revealed the following:
Serum glucose level was significantly increased in the same group before discharge than on
admission; in group II, and group III. Serum glucose level was significantly decreased in
group II and group III on admission as compared to control group, with no significant
difference between serum glucose in group II and group III before discharge and control
group. Serum calcium levels were significantly increased in the same group before discharge
than on admission in group II, and group III. Serum calcium level was significantly decreased
in group II and group III on admission as well as before discharge as compared to control
group.
There was no significant difference between TSB and DSB within the same group before
discharge compared to level on admission; in group II and group III.TSB was higher in IDMs
from PGDM than IDMs from GDM. There was a significant increase in TSB in group II and
group III both on admission and before discharge compared to control group. There was no
significant difference in DSB between group II and group III neither on admission nor before
discharge and the control group.
In conclusion our results indicate that some of the biochemical changes in IDMs (calcium and
glucose) were improved with admission while for bilirubin the rise persist within the same
group .On the other hand when compared to control, the reversibility in hypocalcaemia and
hyperbilirubinemia tend to be slower than the reversibility of hypoglycemia.
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