My Thesis

‫ﺑﺑﺴﻢ اﷲ اﻟﻟﺮﺣﻤﻤﻦ اﻟﺮﺮﺣﻴﻢ‬
‫ﻳﺔ ‪1‬‬
‫‪114‬‬ ‫ﻃﻪ‪ -‬ﺁ ﺔ‬
‫ﺳﻮرة ﻃ‬
‫ﺳ‬
Acknowledgement
First and foremost thanks to ALLAH
I would like to express my sincere appreciation and gratitude to Prof.

Dr.Ibrahim Mohammady Ibrahim, Professor of Physiology, and former
Head of Physiology department, faculty of Medicine, Cairo University,
for his unlimited encouragement, kind supervision and productive
guidance.
I am greatly thankful and grateful to Prof. Dr.Iman Abd el Salam

Sood Professor of Pediatric and former Head of Pediatric department,
faculty of Medicine, Cairo University, for her keen supervision, kind
help and valuable instructions.
I would like to thank Dr. Nermeen Ahmed Al Desouky, Assistant

professor of Clinical Pathology, faculty of Medicine, Cairo University,
who offered me great help throughout this work.
I would like to express my special thanks and gratitude to Prof Dr.

Hassan Mohamed Eissa, Head of Physiology department, faculty of
Medicine, Cairo University.
Shaimaa Nasr Amin

Abstract
Diabetes mellitus with pregnancy causes increased mortality and morbidity to
both the mother and her offspring .The aim of this study is to investigate the
effect of maternal diabetes on some hematological and biochemical parameters
of their newborn infants. The study population consisted of 60 neonates divided
into 3 groups (each consists of 20 neonates); group I (control group), group II
(Infants of diabetic mothers with pregestational diabetes) and group III (Infants
of diabetic mothers with gestational diabetes).
Routine investigations were performed for these neonates in the form of

measuring serum glucose, calcium, total and direct bilirubin levels, complete
blood count and arterial blood gas analysis; measurements were performed once
for control group just after birth and twice for infants of diabetic mothers
(IDMs) on admission and just before discharge from neonatal intensive care
unit (NICU).
Some of the measured variables are affected in IDMs while others showed no
significant difference as compared to control, and the reversibility of the
affected variables to normal level were not the same on discharge from NICU.
Keywords:
Infants of diabetic mothers, gestational diabetes, pregestational diabetes,

hematological changes, biochemical changes.
LIST OF CONTENTS
Page
• Introduction and Aim of the work 1
• Review of literature
Chapter 1: Diabetes and Pregnancy 3
Chapter 2: Infants of Diabetic Mothers 32
• Subjects and Methods 64
• Results 71
• Discussion 110
• Summary 126
• References 131
• Arabic summary

List of Abbreviations

1, 25(OH)2 D 1, 25 dihydroxy vitamin D
AA Autoantibodies
ABG Arterial Blood Gases
American College of Obstetricians and
ACOG Gynecologists
ADIPS Australian Diabetes in Pregnancy Society
AGA Appropriate for gestational age
Akt serine/ threonine kinase

AMPK AMP-activated protein kinase
ANOVA Analysis of variance
aPKC Activated protein kinase C
ASP Acylation stimulating protein
BM Basal plasma membrane
BMI Body Mass Index
C.O Cardiac output
CaO2 Blood oxygen content
CaR Calcium-sensing receptor
CGRP Calcitonin gene related peptide
CBC Complete blood count
CE Cholesterol esters
CETP Cholesterol ester transfer protein
CO Carbon monoxide
CT Calcitonin
CTR CT receptors
DAG Diacylglycerol
DO2 Oxygen delivery
DSB Direct Serum Bilirubin
EFA Essential fatty acid
ELBW Extremely low birth weight
EPO Erythropoietin
ER Endoplasmic reticulum
FFA Free Fatty Acid
GA Gestational age
i


GAD65A Glutamic acid decarboxylase -directed against the
65 K isoform of glutamic acid
GDM Gestational diabetes mellitus
GI Glycemic Index
GLUTs Glucose transporters
Gs stimulating G protein
GSIS Glucose stimulated insulin secretion
HAPO Hyperglycemia and Adverse Pregnancy Outcome
Hb Hemoglobin
HbA Adult haemoglobin
HbA1c Glycosylated hemoglobin
HbF Fetal haemoglobin
Hct Hematocrit
HDL High density lipoprotein
HIF Hypoxia-inducible factor
HL Hepatic lipase
HLA Human leukocyte antigen
HR Heart rate
HNF1A Hepatocyte nuclear factor-1alpha
hPL Human placental lactogen
IA-2A Insulinoma associated antigens
iCa Ionized Ca
ICAs Islet cell cytoplasm
IDMs Infants of diabetic mothers
IGF-1 Insulin like growth factor 1
IGFR Insulin growth factor receptor
IGFBP-1 Insulin like growth factor binding protein-1
IGT Impaired Glucose Tolerence
INDMs Infants of non diabetic mothers
IR Insulin receptor
IRS-1 Insulin receptor substrate-1
IRTK Insulin receptor tyrosine kinase
IUGR Intrauterine growth restriction
KBs Ketone Bodies
ii


Potassium inwardly rectifying channel subfamily J,

KCNJ11 Member 11
LADA latent autoimmune diabetes of the adult
LCPUFA Long-chain polyunsaturated fatty acid
LDL Low density lipoprotein
LGA Large for gestational age
LPL Lipoprotein lipase
MAPK Mitogen activated protein kinase
MCH Mean Corpuscular Hemoglobin
MCHC Mean Corpuscular Hemoglobin Concentration
MCV Mean corpuscular volume
MODY Maturity onset diabetes of the young
MR Mitral regurge
NBS New Ballard score
NEFA Non-esterified fatty acids
NF-κB Nuclear factor-κB
NGT Normal Glucose Tolerance
NICU Neonatal Intensive Care Unit
NZSSD New Zealand Society for the Study of Diabetes
ox-LDL Oxidised low-density lipoprotein
P Phosphorus
PC-1 Plasma cell membrane glycoprotein-1
PCOS Polycystic ovary syndrome
PGDM Pregestational diabetes mellitus
PIP3 Phosphatidylinositol (3, 4, 5)-trisphosphate
PKC Protein kinasesC
PMNL Polymorphonuclear Leukocytes
PNA Postnatal age
PPAR-α Peroxisome proliferator-activated receptor -alpha
PR Pulmonary regurge
PTH Parathyroid hormone
PTHrP PTH-related protein
Ptcco2 Transcutaneous measurement of Pco2
iii


PVH Pathologic ventricular hypertrophy
RDS Respiratory Distress Syndrome
RDW RedCell Distribution Width
SaO2 Hemoglobin saturation
SD Standard Deviation
SGA Small for gestational age
SOD Superoxide dismutase
Spo2 Pulse oximetry oxygen saturation
SPSS Statistical Package for the Social Science
STfR Serum transferrin receptors
SV Stroke volume
TAS Total antioxidant status
tCa Total Ca concentrations
TCR T-cell receptor
TfR-F index Transferrin receptors to ferritin ratio
TG Triglyceride
TK Tyrosine kinase
TLC Total Leukocytic Count
TNF-α Tumour necrosis factor-alpha
TR Tricuspid regurge
TSB Total Serum Bilirubin
TReg T regulatory cells

TTN Transient Tachypnea of the Newborn
UCP Uncoupling protein
UDPGT Uridine diphosphoglucuronosyl transferase
Uridine diphosphoglucuronate
UGT Glucuronosyltransferase
UGT1A1 a specific enzyme A1 isoform of UGT
VEGF Vascular endothelial growth factor
VLDL Very low density lipoprotein
WHO World Health Organization
iv

List of Tables

Tables of Review of literature
Table Title Page
No.
1 Priscilla White’s last classification for diabetes in 8
pregnancy modified by Pedersen
2 Recommended values for the diagnosis of gestational 29
diabetes
3 Normal Hemoglobin levels in neonates 56
Tables of the Results

Table Title Page
No.
1 Shows mean ±standard deviation (SD) of the measured 71-
variables among studied groups 72
2 Paired Sample test for serum glucose and calcium at 73
admission and before discharge (Group II)
3 Paired Sample test for Arterial blood gas analysis 74
components at admission and before discharge (Group II)
4 Paired Sample test for total and direct bilirubin at admission 74
and before discharge (Group II)
5 Paired Sample test for complete Blood Count among at 75
admission and before discharge (Group II)
6 Paired Sample test for serum glucose and calcium at 76
admission and before discharge (Group III)
7 77
Paired Sample test for Arterial blood gas analysis
components at
8 Paired Sample test for total and direct bilirubin at admission 77
v

List of Tables

and before discharge (Group III)
9 Paired Sample test for Complete Blood Count among at 78
10 Comparison of serum glucose and calcium in group II, group 79
III on admission and control group.
11 Comparison of Arterial Blood Gas analysis in group II, 80
group III on admission and control group.
12 Comparison of total and direct serum bilirubin in group II, 81
group III on admission and control group
13 Comparison of Complete Blood Count in control, group II 82
on admission and group III on admission
14 Comparison of serum glucose and calcium in, group II, 83
group III before discharge and control group.
15 Comparison of Arterial Blood Gas analysis in group II, 84
16 Comparison of total and direct serum bilirubin in group II , 84
group III before discharge and control group
17 Comparison of Complete Blood Count in, group II, group III 86
before discharge and control group
18 No significant correlation between serum glucose levels TSB 95
in control group (group I)
19 A significant positive correlation between serum glucose 96

level and total serum bilirubin in group II on admission
20 No significant correlation between serum glucose (mg/dl) 97
levels and TSB (mg/dl) in groupIII on admission (groupIII a)
21 No significant correlation between gestational age and total 98

leucocytic count in control group (group I)
vi

List of Tables

leucocytic count group II on admission (group IIa)

leucocytic count in groupIII on admission (group IIIa)
24 No significant correlation between staff count and 101

gestational age in control group (group I)
gestational age in group II on admission (group IIa)

gestational age in groupIII on admission (group IIIa)
27 No significant correlation between reticulocytic index and 104

28 A significant positive correlation between reticulocytic index 105

and gestational age in group II on admission (group IIa)
30 No significant correlation between total serum bilirubin and 107


vii

List of Figures

Figures of Review of literature
Figure Title Page
No.
1 Overview of maternal /fetal nutrient transport and 3
availability
2 Relationship of adipose tissue lipolytic activity with 7
lipoprotein
3 Intermediary metabolism in non-pregnant ,normal 16
pregnancy and gestational diabetes
4 Summary of Potential Mechanisms of insulin resistance in 19
skeletal muscle during late pregnancy in human gestational
diabetes
5 Scheme depicting the putative sequence of events that may 23
take place in women with autoimmune gestational diabetes
mellitus (GDM)
6 Problems found in IDMs 32
7 Obesity and impaired glucose tolerance in offspring of 37
diabetic mothers
8 Hemoglobin switching 55
9 chemical structure of naturally occurring unconjugated 59
bilirubin
Figures of Subjects and Methods

Figure Title Page
No.
1 New Ballard Score 66
viii

List of Figures

Figures of the Results
Figure Title Page
No.
1 Comparison of plasma glucose level (mg/dl) among the 87
studied groups
2 Comparison of plasma calcium level (mg/dl) among the 87

studied groups
3 Comparison of serum total bilirubin (mg/dl) level among the 88

studied groups
4 Comparison of serum level of direct bilirubin (mg/dl) among 88

the studied group
5 Comparison of hemoglobin level among the studied group 89
6 Comparison of packed cell volume (%) among the studied 89

group
7 Comparison of total leucocytic count among the studied 90

group
8 Comparison of staff. Count among the studied group 90

9 Comparison of platelets counts among the studied group 91
10 Comparison of red cell distribution width among the studied 91

group
11 Comparison of oxygen tension (mm Hg) among the studied 92

group
12 Comparison of carbon dioxide tension among the studied 92

group
13 Comparison of bicarbonate level among the studied group 93
14 Comparison of pH among the studied group 93
ix

List of Figures

15 Comparison of base deficit/excess among the studied group 94

16 No significant correlation between serum glucose level TSB 95
in control group (group I)
17 A significant positive correlation between serum glucose 96

level and total serum bilirubin in group II on admission
18 No significant correlation between serum glucose (mg/dl) 97

levels and TSB (mg/dl) in groupIII on admission (group
IIIa)

leucocytic count in control group (Group I)

leucocytic count in group II on admission (group IIa)


26 A significant positive correlation between Reticulocytic 105

index and gestational age in group II on admission (group
IIa)
x

List of Figures



xi

Introduction and aim of the work

Introduction
Diabetes mellitus during pregnancy increases fetal and maternal
morbidity and mortality (Walkinshaw, 2005). 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 (Moses and Cheung,
2009) and varies in direct proportion to typeII diabetes mellitus in the
background population (Ben-Haroush et al., 2004).
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 midpregnancy and progresses through the third trimester to the level that
approximates the insulin resistance seen in individuals with type II diabetes
mellitus (Lain and Catalano, 2007).The insulin resistance appears to result
from a combination of increased maternal adiposity and the placental secretion
of anti-insulin hormones (Stuebe et al., 2009).
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 (Stuebe et al., 2009). If
there is maternal defect in insulin secretion and in glucose utilization, GDM will
occur as the diabetogenic hormones rise to their peak levels (Negrato et al.,
2009). Abnormal concentrations of maternal glucose, lipids, and amino acids
may influence fetal development, leading to changes in metabolism, weight, and
behaviour. Congenital anomalies are more frequent in infants of diabetic
mothers. Increased glucose metabolism in embryo cells increases oxidative
stress through hexosamine biosynthetic pathway (Horal et al., 2004) or hypoxia
(Li et al., 2005). Fetal organogenesis is completed by seven weeks
1

Introduction and aim of the work

postconception and there is an increased prevalence of congenital anomalies and

spontaneous abortions in diabetic women with poor glycaemic control during
this period (Eriksson, 2009).
If the mother has hyperglycaemia, the fetus will be exposed to either

sustained or intermittent hyperglycaemia. Before 20 weeks’ an acute
hyperglycaemic 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
(Ericsson et al., 2007).
The fetus may have cardiac arrhythmia due to decreased potassium level
with elevated insulin and glucose levels (De Leon and Stanley, 2007). 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 (Georgieff, 2006).
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 ,
hypoglycaemia, adverse neurodevelopment outcomes, congenital anomalies,
hypocalcaemia, hypomagnesaemia, and iron abnormalities, cardiovascular
malformations(Alam et al., 2006; Barnes-Powell ,2007).
-Aim of the work:
The aim of this study is to investigate the effect of maternal diabetes on

some hematological and biochemical parameters of their offspring.
2

Chapter I Review of Literature
L

DIAB
BETES AND
A PR
REGNA
ANCY
Metabolism in normaal pregnaancy

Metabolicc adaptattions duriing pregn
nancy aree essentiaal to meeet the
physioological deemands off pregnanccy, adequ
uate growtth and devvelopmentt of the
fetus. During thhe first week
w of deevelopmen
nt, the em
mbryo most likely obtains
o
nutriennts by sim
mple diffuusion from
m blood pooled in the
t trophooblastic laacunae.
Howevver, the metabolic
m d
demands of the dev
veloping embryo
e sooon outstrrip this
means of nutrient deliveery and progressiv
p ve placenntal develoopment and
a the
establiishment of uteroplaacental annd fetoplaccental circculations pprovides a more
efficient means of materrnofetal exchange
e (Glazier and Jansson, 200
04).The
placennta processses signals sent by the materrnal and fetal
fe organnisms to reegulate
fetal demand
d annd maternaal substratte supply, ensure its own meetabolic deemands
and traansfer fetaal waste innto the maternal circculation (vvon Verseen-Hoeyncck and
Powerrs, 2007).
Figuree (1): Oveerview of maternall /fetal nu

utrient traansport an
nd availab
bility
(von Versen-Ho
V oeynck an
nd Powerrs, 2007)
3


-Carbohydrate metabolism
Glucose is the primary energy source of fetoplacental tissues. During

early pregnancy, basal plasma glucose, insulin and hepatic gluconeogenesis are
unchanged. However, during late pregnancy; the mother develops
hypoglycemia, which is especially manifest under fasting conditions, when the
rate of gluconeogenesis from different substrates is enhanced. The development
of maternal hypoglycemia despite the enhanced gluconeogenesis and the
reduced consumption of glucose by maternal tissues in presence of insulin
resistance is due to the high rate of placental transfer of glucose (von Versen-
Hoeynck and Powers, 2007). The use of different substrates for
gluconeogenesis using glycerol rather than other gluconeogenetic substrates is
intense (Hadden and McLaughlin, 2009).
Glucose transfer is carried out by facilitated diffusion according to

concentration-dependent kinetics in presence of a high number of glucose
transporters (GLUTs), particularly GLUT1. GLUT4 is an insulin-responsive
glucose transporter, and is present in placental stroma. GLUT8 is expressed by
the placenta at term, but may be of less importance in early pregnancy
(Limesand et al., 2004). At term, GLUT12 is found predominantly in villous
vessel smooth muscle cells and villous stromal cells (Gude et al., 2005).
The fetus does not synthesize glucose but uses it as its main oxidative
substrate. This causes fetal glycemia to be normally lower than that of its
mother allowing a positive maternal–fetal glucose gradient, which facilitates its
placental transfer (Limesand et al., 2004).
When the fetus is deprived of glucose by placental insufficiency or
maternal hypoglycemia, fetal weight-specific glucose utilization rate is not very
much different from normal rates. This occurs by increasing concentrations,
activity and plasma membrane localization of glucose transporters that increase
insulin signal transduction (Wallace et al., 2005). Chronic hyperglycemia
4


down-regulates glucose tolerance and insulin sensitivity with decreased

expression of skeletal muscle and hepatic Glut 1 and 4 glucose transporters
(Hay, 2006).
-Protein and amino acid metabolism
The accretion of protein is essential for fetal growth and must be

sustained by the active transfer of amino acids from maternal circulation. There
is no evidence that pregnant women store protein during early pregnancy, when
fetal needs are scarce. Therefore, the increased requirements of late pregnancy
must be met by metabolic adjustments that enhance both dietary protein
utilization and nitrogen retention in order to satisfy fetal demands. Protein
metabolism changes gradually throughout gestation, so that nitrogen
conservation for fetal growth achieves full potential during the last quarter of
pregnancy (Hadden and McLaughlin, 2009).
The rate of maternal nitrogen retention between 20 and 40 weeks of

gestation was greater than predicted, due to a reduction in urinary nitrogen
excretion because of decreased urea synthesis. In late pregnancy, nitrogen
balance is improved, with more efficient use of dietary proteins .Although these
alterations that favor nitrogen conservation, pregnancy is associated with
hypoaminoacidemia, which is more evident during fasting and reflects enhanced
placental amino acid uptake (von Versen-Hoeynck and Powers, 2007).
Contrary to glucose, the concentration of most amino acids in fetal

plasma is higher than that found in the mother, and placental transfer of amino
acids is carried out by an active process, using selective transporters and
metabolic energy (Herrera, 2005).
5


-Lipid metabolism
Fat accumulation occurs during the first two trimesters and represents
most of the increase in maternal structures that occurs during pregnancy. It is
the result of both hyperphagia and enhanced lipid synthesis driven by the
enhanced adipose tissue insulin responsiveness .Increments of maternal fat
depots stop in the third trimester, with an increased adipose tissue lipolytic
activity, which is especially manifest under fasting conditions (Toescu et al.,
2004).
The placental transfer of the products of lipolysis released into the

circulation, non-esterified fatty acids (NEFA) and glycerol is low, and their
main destiny is maternal liver where NEFA are converted into acyl-CoA, and
glycerol into glycerol-3-phosphate, which are partially re-esterified for the
synthesis of triacylglycerols. These are released back into the circulation in the
form of very low density lipoprotein (VLDL), as maternal liver production is
enhanced. Whereas glycerol is also used as a preferential substrate for
gluconeogenesis, NEFA are used for β-oxidation, leading to energy production
and ketone body synthesis. Ketone bodies easily cross the placenta .Although
not synthesized by the fetus, in fetal circulation, they reach the same
concentration as in the mother (Herrera, 2005).
There is change in low density lipoprotein (LDL) profile towards smaller

species and the decrease in serum total antioxidant status (TAS) with increased
levels of oxidised low-density lipoprotein (Ox-LDL)( Belo et al., 2004).
6


Fig (2): Relationship of adipose tissue lipolytic activity with lipoprotein

(EFA=essential fatty acid, LCPUFA= long-chain polyunsaturated fatty
acid, CETP=cholesterol ester transfer protein, CE=cholesterol esters,
HDL=high density lipoprotein, LDL=low density lipoprotein, VLDL=very
low density lipoprotein, LPL=lipoprotein lipase, HL=hepatic lipase,
KBs=Ketone Bodies (Herrera, 2005).
7


-Classification of diabetes during pregnancy

The White classification system for diabetes in pregnancy, developed in
1949, is based on age of onset and duration of disease, as well as disease
progression with respect to vascular complications (Hare, 1994).
Class Description
A1 Diet-controlled gestational diabetes
A2 Insulin-treated gestational diabetes
B Onset at age 20 years or older and duration of less than 10 years
C Onset at age 10-19 years or duration of 10-19 years
D Onset before 10 years of age, duration over 20 years,
benign(background) retinopathy, or hypertension (not
preeclampsia)
D1 Onset before age 10 years
D2 Duration over 20 years
D3 Calcification of vessels of the leg (macrovascular disease), formerly
called Class E
D4 Benign retinopathy (microvascular disease)
D4 Hypertension (not preeclampsia)
R Proliferative retinopathy or vitreous hemorrhage
F Nephropathy with over 500 mg/day proteinuria
RF Criteria for both classes R and F
G Many pregnancy failures
H Evidence of arteriosclerotic heart disease
T Prior renal transplantation
Table (1): Priscilla White’s last classification for diabetes in pregnancy
modified by Pedersen (Hare, 1994).
*All classes following Class A require insulin therapy.* Classes R, F, RF, H
and T have no onset/duration criteria but usually occur in long-term diabetes.
8


GESTATIONAL DIABETES MELLITUS
Gestational diabetes mellitus (GDM) is defined as an impairment of

glucose tolerance first recognised during pregnancy. GDM occurs in 2.2%–
8.8% of pregnancies, depending on the ethnic mix of the population and the
criteria used for diagnosis (Theodoraki and, Baldeweg, 2008). The incidence
of GDM is increasing, in parallel to the increase in type 2 diabetes (Ben-
Haroush et al., 2004).
-Mechanisms leading to the development of gestational diabetes
The mechanisms leading to the development of gestational diabetes

mellitus (GDM) are probably related to an exacerbation of the beta-cell
dysfunction in subjects genetically predisposed to beta-cell alterations. Several
mechanisms could be involved, with high progesterone levels may play a
relevant role (Buchanan and Xiang, 2005; Xu et al., 2008).
The hyperlipidemia during pregnancy may decrease the capability of beta

cells to secrete insulin (Kasuga, 2006; Ethier-Chiasson et al., 2008).Although
fatty acids may induce insulin secretion (Rojo-Martinez et al., 2006; Laura
Lee et al., 2009), prolonged high levels of fatty acids may damage the beta cell,
through activation of endoplasmic reticulum(ER) stress (Laybutt et al., 2007;
Lai et al., 2008; Mühlhausler, 2009). In certain genetically predisposed
subjects, the higher supply of glucose and fatty acids to the beta cell may
increase the cell metabolism, with glucose augments lipotoxicity through
amplification of the ER stress response, leading to increased beta-cell apoptosis
and cell death. Beta cells fail to secrete enough insulin in a period of high
insulin requirements together with development of insulin resistance, leads to
the development of GDM( Prentki and Nolan, 2006; Bachar et al., 2009).
9


Hormonal effects in normal and diabetic pregnancy
-Estrogen and progesterone
In early pregnancy, both progesterone and estrogen rise but their effects
on insulin activity are counterbalanced. Progesterone causes insulin resistance
whereas estrogen is protective. In cultured rat adipose tissue, treated with
estrogen, there was no effect on glucose transport, but maximum insulin binding
was increased. However, progesterone decreased both maximum glucose
transport and insulin binding (Waters et al., 2009).
Moreover, estrogens help the adaptation of the islets of Langerhans to the

high glucose stimulated insulin secretion (GSIS) and increase beta-cell mass,
which increase insulin biosynthesis and secretion (Nadal et al., 2009).
-Cortisol
Cortisol levels increase as pregnancy advances and by the end of

pregnancy concentrations are threefold higher than in the non-pregnant state
(Lindsay and Nieman, 2005). Under conditions of high amounts of cortisol,
hepatic glucose production is increased and insulin sensitivity decreased with
development of insulin resistance and beta-cell dysfunction (Bernal-Mizrachi
et al., 2007).
The nuclear receptor peroxisome proliferator-activated receptor -alpha

(PPAR-α) plays an important role in cortisol-induced hepatic insulin resistance
and hyperglycaemia (Bernal-Mizrachi et al., 2007).PPAR-α, is predominantly
expressed in the liver acting as a fatty acid sensor and it is a major regulator of
energy homeostasis by promoting fatty acid oxidation, gluconeogenesis and
ketogenesis (Van Raalte et al., 2004).
10


-Prolactin
During pregnancy, maternal prolactin levels increase 7- to10-fold. The

basal insulin concentration and post-challenge glucose and insulin responses
were greater in women with hyperprolactinemia than in healthy controls.
Prolactin shares in the adaptation to insulin resistance during pregnancy through
increasing beta-cell mass (Amaral et al., 2004, Grattan et al., 2008). This
participation is mediated through its action on prolactin receptors and
phosphatidylinositol 3-kinase and mitogen activated protein kinase (MAPK)
pathways (Huang et al., 2009).
-Human placental lactogen
Human placental lactogen (hPL) levels rise at the beginning of the second
trimester, causing a decrease in phosphorylation of insulin receptor substrate-1
(IRS-1) and profound insulin resistance (Freemark, 2006).
-Leptin
Leptin is a protein, secreted by adipose tissue. It can modulate energy

expenditure by direct action on the hypothalamus. Receptors to leptin are found
in skeletal muscle, liver, pancreas, adipose tissue, uterus and the placenta; this is
responsible for both peripheral and central insulin resistance. Reductions in
leptin concentrations are caused by weight loss, fasting, while leptin
concentrations are increased with weight gain and hyperinsulinemia. Leptin
directly affects whole body insulin sensitivity by regulating the efficiency of
insulin mediated glucose metabolism by skeletal muscle, and by hepatic
regulation of gluconeogenesis. Leptin may also exert an acute inhibitory effect
on insulin secretion (Coll et al., 2007).
11


Leptin levels are significantly higher in pregnancy than in the non-

pregnant state, especially during the second and third trimesters; this is
consistent with changes in maternal fat stores and glucose metabolism. Plasma
leptin was higher in the women with GDM than in the women with normal
glucose tolerance, and higher in both these groups than in the non-pregnant
controls (Henson and Castracane, 2006; Briana and Malamitsi-Puchner,
2009). Umbilical cord leptin concentration was an independent risk factor for
fetal macrosomia in non-diabetic women (Hauguel et al., 2006), in GDM cord
blood leptin levels are significantly higher, and a source other than fetal
adipocytes appears to contribute to this rise (Okasha et al., 2007).
-Adiponectin
Adiponectin is an adipose tissue hormone that facilitates the regulation of

the glucose and lipid metabolism. Adiponectin suppresses the secretion of TNF-
α by adipose tissue, decreases the hepatic glucose production and insulin
resistance by enhancing the beta oxidation of free fatty acids and by decreasing
the intracellular concentrations of triglycerides (Williams et al., 2004).
A cord blood adiponectin level was extremely high in comparison to

serum levels in children and adults and was positively correlated to fetal birth
weights. No correlation was found between cord adiponectin levels and
maternal body mass index, cord leptin, or insulin levels. Serum adiponectin
level was significantly lower in gestational diabetes in comparison with healthy
pregnant both in pregnancy, as well as postpartum women (Ranheim et al.,
2004; Soheilykhah et al., 2009). Significant reduction in adiponectin level was
observed postpartum in GDM (Vitoratos et al., 2008).Mode of delivery didn’t
influence levels of adiponectin and insulin in IDMs (El Sheemy et al., 2008).
12


-Tumour necrosis factor-alpha
Tumour necrosis factor-alpha (TNF-α) is involved in regulation of

glucose and lipid metabolism and the pathogenesis of insulin resistance in
pregnancy, pathogenesis and progression of GDM (Altinova et al., 2007).
There is an increased TNF-α genes expression in adipose tissue of

pregnant women with gestational diabetes (Kuźmicki et al., 2006).
-Adrenomedullin
Placental adrenomedullin is a hypotensive peptide upregulated in diabetic

pregnancy and that it may be important to prevent excessive vasoconstriction of
placental vessels (Sekine et al., 2006).It is involved in the insulin regulatory
system and it may play a role in modifying diabetes in pregnancy. At picomolar
concentrations it directly inhibits insulin secretion from beta-cells (Harmancey
et al., 2007).
13


Maternal Metabolic Changes in Gestational Diabetes Mellitus
-Glucose metabolism alterations in GDM
Because the maternal-fetal transfer of glucose is concentration-dependent,

under conditions of maternal hyperglycemia and normal placental function,
there is increased placental transfer of glucose .Fetal hyperglycemia develops
and secondary to this alteration, hyperinsulinism occurs. The hyperinsulinism
remains in the neonatal period and increases the risk of hypoglycemia once the
umbilical supply of glucose is suddenly arrested after delivery. The newborn
will need frequent monitoring of blood glucose, early feeds and may require the
intravenous administration of glucose (Persson, 2009).
-Amino acid metabolism alterations in GDM
In GDM, there is an increase in a number of essential and nonessential

amino acids in umbilical venous and arterial concentration compared to the
values found in normal pregnancies. The higher plasma levels of fetal amino
acids do not seem to be related to a higher concentration in maternal plasma, as
only ornithine has been shown to increase in plasma from pregnant women with
GDM (Cetin et al., 2005). Second trimester increase in maternal serum
homocysteine has been reported and this suggests that placental amino acid
exchange and/or fetoplacental metabolism is altered in GDM (Guven et al.,
2006).
Among the different amino acid transporters, the expression of system A,

which mediates the transfer of neutral amino acids such as alanine, serine, and
glutamine, is increased in diabetic pregnancies. Specific system for leucine
(system L), have also been shown to be increased in microvillous plasma
membranes isolated from GDM pregnancies with large babies for their
gestational age (Jansson and Powell, 2006).
14


Leucine has been proven to be an effective stimulus for fetal insulin

secretion in human pancreas studied in vitro (Jansson and Powell 2006; Liu et
al., 2008), a rise in glucose concentration is necessary for leucine to stimulate
significant insulin secretion (Kalogeropoulou et al., 2008).
-Lipid metabolism alterations in GDM
Higher levels of triglycerides and cholesterol are pro-oxidant and this

leads to increased LDL oxidation, but this effect may be blunted by higher
levels of vitamin E and estradiol whose levels are increased in pregnancy. A
correlation between LDL oxidation and birth weight, suggesting that conditions
where LDL oxidation is increased, fetal growth may be compromised
(Sánchez-Vera et al., 2005). The small, dense LDL particles are associated
with insulin resistance (Goff et al., 2005; Herrera, 2005), and with a 4-fold
increased risk of GDM (Qiu et al., 2007).
In GDM as in other conditions of insulin resistance and beta-cell

dysfunction, there is an increase in plasma levels of triglycerides and cholesterol
(DiCianni et al., 2005).
The acylation stimulating protein (ASP) is a potent lipogenic adipokine

that correlates with postprandial triglyceride clearance .Maternal
hypertriglyceridemia is associated with increased fetal ASP production, thus
enhancing fetal fat storage independent of maternal glucose variations in non
diabetic women(Saleh et al.,2008).
15


16


Insulin signalling system in normal pregnancy and in gestational diabetes

mellitus
The mechanisms involved in pregnancy-induced insulin resistance are

related to different factors. There are several hormonal and metabolic alterations
that lead to insulin resistance. These includes hypertriglyceridemia , TNF-alpha,
high levels of progesterone found in the second half of pregnancy, and
decreased adiponectin levels(DiCianni et al., 2005;Vitoratos et al., 2008).
-Insulin Receptor
The action of insulin is triggered when it binds to the insulin receptor

(IR). The IR belongs to the insulin growth factor receptor (IGFR) family, which
has an intrinsic tyrosine kinase (TK) activity. The IR is composed of two alpha
subunits, each linked to a beta subunit and to each other by disulfide bonds;
only the beta subunit has enzymatic TK activity. When insulin binds to the
receptor, the conformational change activates the beta-subunit with
autophosphorylation of cellular substrates. Insulin Receptor Substrate-1 (IRS-
1), a cytosolic protein, binds to the phosphorylated intracellular substrates,
transmitting the insulin signal downstream. A single insulin molecule can
contact both alpha subunits in the insulin receptor dimer during high affinity
binding (Chan et al., 2007).
In GDM, the skeletal muscle contains less IRS-1and significantly less

insulin-stimulated IRS-1 tyrosine phosphorylation, while levels of the IRS-2 are
increased. This suggests that the insulin resistance of GDM may be exerted
through a decrease in the insulin signal cascade at the level of the IRS. The
increased IRS-2 level may be a compensation for the reduced IRS-1 level (Qu
et al.,2007).Post receptor defects are present in the insulin signalling pathway in
17


placenta of women with pregnancies complicated by diabetes and obesity

(Colomiere et al.,2009).
The insulin resistance of normal pregnancy is multifactorial, involving

reduced ability of insulin to phosphorylate the IR, decreased expression of IRS-
1, and increased levels of the p85α subunit of PI 3-kinase. IRS-1 is further
decreased in most GDM subjects compared with obese pregnant women at term.
However, in GDM, there are reciprocal and inverse changes in the degree of
serine and tyrosine phosphorylation of IR and IRS-1 that further inhibit
signaling, leading to substantially reduced GLUT4 translocation and decreased
glucose uptake beyond that of normal pregnancy. Women with a history of
GDM have evidence of subclinical inflammation and there is evidence for
increased TNF-α. Adiponectin, a key insulin-sensitizing hormone produced by
adipose tissue, is significantly lower in women with a history of GDM and
declines with advancing gestation, suggesting it could be involved in the
transition to insulin resistance. In adipose tissue, the lipogenic transcription
factor PPAR-γ declines in obese women during pregnancy and may shift genes
in metabolic pathways to favor increased lipolysis, thus accelerating adipose
tissue insulin resistance and the switch from lipid storage to lipolysis. This
transition to insulin resistance contributes to greater postprandial increases in
FFAs and increased hepatic glucose production and results in greater fuel
availability to the fetus of women with GDM. Thus, like a perfect storm,
subclinical inflammation, placental hormones, reduced adiponectin secretion,
and excess lipolysis conspire to cause severe insulin resistance in liver, muscle,
and adipose tissue in women with GDM (Barbour et al., 2007).
18

L

Figuree (4): Su
ummary of Potenttial Mech
hanisms of insulin
n resistance in
skeletaal musclee during late pregn
nancy in human
h geestational diabetes (TNF-
α=Tum K=AMP-aactivated protein kinase,
mor Necrrotic Factor alphaa, AMPK k
PIP3=
= Phosphaatidylinossitol (3, 4,, 5)-trisph
hosphate,, Akt=seerine/ thrreonine
kinasee, aPKC=
=activated
d protein kinase
k C, IRS=Inssulin Receeptor Sub
bstrate,
Glut=Glucose Transpor
T ter) (Barb
bour et all., 2007).
-Glucoose Transsporters
Glucose uptake
u byy cells is mediated
m mily of meembrane proteins
by a fam p
(GLUT
T). GLUT
T4 is the main insuulin-sensittive glucoose transpporter, exp
pressed
uniqueely in skeeletal andd cardiac muscles and adippose tissuue. The insulin-
i
stimulated glucose transpport and the GLUT
T4 contennt in adippose tissue were
reduceed at term
m in womeen with GD
DM, with
hout alteraations in pplacental glucose
g
transpoort (Lindaa et al., 20007).
-plasm
ma cell meembrane glycoprottein-1 (PC
C-1)
The mem ma cell membrane glycoprote

mbrane prootein plasm g ein-1 (PC-1) has
been identifiedd as an inhibitor of insullin recepttor TK ((IRTK) activity
a
19


(Stefanović and Antić, 2004). PC-1 overexpression impairs insulin stimulation

of insulin receptor (IR) activation and downstream signalling. PC-1 binds to the
connecting domain of the IRα -subunit that is located in residues 485–599. The
connecting domain transmits insulin binding in α -subunit to activation of
tyrosine kinase activation in the β-subunit. When PC-1 is overexpressed, it
inhibits insulin-induced IR β-subunit tyrosine kinase activity. In addition, a
polymorphism of PC-1 (K121Q) in various ethnic populations is closely
associated with insulin resistance. The product of this polymorphism has a 2- to
3-fold increased binding affinity for the IR and is more potent than the wild type
PC-1 K in inhibiting the IR (Ira et al., 2008).
-The peroxisome proliferator-activated receptors (PPARs)
The peroxisome proliferator-activated receptors (PPARs) are a family of

fatty acid sensors, which transduce stimuli from fatty acids into changes in gene
expression. PPARγ is highly expressed in adipose tissue and plays an essential
role in the regulation of insulin sensitivity. The target genes induced by PPAR
include (among others) adiponectin, lipoprotein lipase, the intracellular fatty
acid binding protein aP2, and the mitochondrial uncoupling protein UCP2
(Qiao et al., 2005). The PPAR-γ2 Pro12Ala polymorphism in patients with
GDM gained significantly more weight during their pregnancy (Tok et al.,
2006).
20


-Risk Factors in development of GDM
1-Genetic Factors
Genetic predisposition to GDM has been suggested since GDM clusters

in families. Also, women with mutations in MODY (Maturity onset diabetes of
the young) genes often present with GDM. In addition, common variants in
several candidate genes (e.g. potassium inwardly rectifying channel subfamily J,
member 11 [KCNJ11], hepatocyte nuclear factor-1alpha [HNF1A] etc.) have
been demonstrated to increase the risk of GDM (Shaat and Groop, 2007).
Mutations in the glucokinase gene occur in no more than 5% of GDM patients
(Okruszko et al., 2007).
Human leukocyte antigen-G (HLA-G) expression that functions to protect

the fetus from immune attack by down-regulating cytotoxic T cell responses to
fetal trophoblast antigens is postulated to protect the islet cells of the pancreatic
tissue also. HLA-G and nuclear factor-κB (NF-κB) interaction is suggested to
be central in the events leading to GDM development (Oztekin, 2007).
2-Immunological Factors
Pregnancy represents a distinct immunologic state; the fetus acts as an

allograft to the mother, needs protection against potential rejection. The final
effect of pregnancy on previously active autoimmune processes is controversial,
and multiple autoimmune disturbances may be manifested during pregnancy
specific to other organs: thyroid, adrenal cortex and gastric mucosa
(Jurczyńska and Zieleniewski, 2004).
Humoral immunoreactivity does not change much during pregnancy, with

the exception of lowered immunoglobulin G concentration at late phase,
probably explained by placental transport. Site-specific suppression, in which
21


maternal immune responses are controlled locally at the maternal- fetal

interface, plays a fundamental role in controlling maternal allogeneic immune
responses (Cody et al., 2007).
Regarding cellular immunity, CD4+ CD25+ T regulatory cells (TReg)

suppress antigen-specific immune responses and are important for allograft
tolerance. Normal pregnancy is associated with an elevation in the number of
TReg cells which may be important in maintaining materno-fetal tolerance
(Somerset et al., 2004).
-Autoimmune gestational diabetes
Some GDM patients depicting humoral autoimmune markers against

pancreatic cells, express several autoantibodies (AA) against various pancreatic
islet cell autoantigens, typically detected in Type 1 diabetes (Ben-Haroush et
al., 2004).
-Islet-cell autoantibodies
Islet cell autoantibodies (AA) include AA to islet cell cytoplasm (ICAs);

to native insulin (IAAs); to glutamic acid decarboxylase (GAD65A)-directed
against the 65 K isoform of glutamic acid decarboxylase and to two tyrosin
phosphatases (insulinoma associated antigens IA-2A and IA-2βA) with a higher
prevalence of ICA than other AAs (Damanhouri et al., 2005).
The titres of the different autoantibodies have been shown to be lower

than in type 1 and pre-type 1 relative. These autoantibodies have also been used
to identify high-risk individuals for the development of the disease, specifically
first-degree relatives of subjects with type 1 DM (Järvela et al., 2006).
There is an increased risk of DM-1 in women with GDM and positivity

for ICA, GADA and with the risk increasing with the number of AAs. The
22

L

autoim
mmune proocess leadding to tyype 1 DM
M is preciipitated byy environ
nmental
factorss operatinng on a geneticall
g y predisp
posed individual (L
Löbnner et al.,
2006)..
Although the majoority of women

w deeveloping diabetes after GDM
M will
show type
t 2 DM
M, a low but ortion will develop type 1 DM
b significcant propo M. The
latter are
a women in whicch an autooimmune pathogeni
p c pathwayy lies behind the
presennce of gluucose intolerance duuring preg
gnancy. Women
W w
with autoim
mmune
GDM who later developp any of the
t clinicaal forms of type 1 DM sho
ould be
considdered pre-ttype 1 diaabetic indiividual ideentified duuring preggnancy (H
Hansen
et al., 2005;
2 Lap
polla et all., 2009).
Figuree (5): Sch

heme depiicting the putative sequencee of eventts that ma
ay take
place in womeen with autoimmu
a une gesta
ational diiabetes m
mellitus (G
GDM).
After pregnanccy, women
n may evolve to no
ormal (NG
GT) or im
mpaired glucose
g
toleran
nce (IGT
T). Alterrnatively, they ca
an furtheer progrress to slowly-
s
oimmune diabetess of the adult
progreessive tyype 1 diaabetes/lattent auto
(LADA
A), or to rapid-ons
r set (classiical) type 1 diabetees mellituss (Hansen
n et al.,
2005).
23


3-Body Mass Index (BMI)

Maternal prepregnancy BMI is directly associated with the risk of
developing GDM and is a strong predictor for GDM requiring insulin treatment
(Rudra et al., 2007; Stothard et al., 2009).
Obesity causes major changes in maternal intermediary metabolism, and
insulin resistance appears to play a central role (Ginsberg et al., 2006;
Ghiadoni et al., 2008). Insulin receptors and post-receptor defects associated
with obesity may be further exacerbated by pregnancy (Andreasen et al.,
2004).
Inflammation is another possible explanation for the link between
obesity and GDM, a systemic inflammation seems to be involved as indicated
by higher levels of serum C- reactive protein, interleukin-6 (Qiu et al., 2004)
and ferritin (Chen et al., 2006).As adipocytes secrete proinflammatory
cytokines, inflammation is usually associated with obesity. Therefore, the
abundance of adipocytes in obese women could produce excess inflammatory
markers that in turn would lead to the development of GDM (Kriketos et al.,
2004).
4-Maternal Age
The highest risk for GDM is maternal age. In a prospective study the
relative risk for GDM rose by 4% for each year of age after 25(Williams et al.,
2004).
5-Family History
Maternal inheritance is stronger in GDM unlike type 1diabetes which is
mostly inherited from the father (Tabák et al., 2009). Women with a sibling
history of diabetes were more likely to have GDM than women with other
family history patterns (Kim et al., 2009).
24


6-Smoking
The Increased insulin resistance, hyperinsulinemia and type 2 diabetes
have been linked with cigarette smoking outside of pregnancy in some but not
all studies, but whether cigarette smoking is a risk factor for GDM remains
controversial (England et al.,2004;Wendland et al., 2008).
7-ethnicity
Risk of GDM appears to vary among ethnic groups, particularly more
among Asian women, and most markedly among women from South Central
Asia for whom the risk also is rising over time. The more modestly risk is
among Latin American women. The reasons for differences among ethnic
groups include, genetic variation based on geographic origin, lifestyle and
cultural factors in those countries resulting from different religious and dietary
traditions (Savitz et al., 2008).
8-Poor obstetric outcomes

History of previous GDM is associated with risk of recurrence with rates
of up to 70% have been reported. GDM recurrence rates are influenced by
maternal health characteristics and past pregnancy history (Bottalico, 2007;
Kwak et al., 2008).
Unexplained multiple miscarriages, stillbirths, or birth defects may be
due to undiscovered GDM. Women who have multiple loss history tend to have
increased rates of GDM (Khatun et al., 2009).
9- Polycystic ovary syndrome (PCOS)

The risk of developing GDM in patients with PCOS occurs independent
of obesity (Boomsma et al., 2006; Kashanian et al., 2008).This is consistent
25


with the known association of PCOS and glucose intolerance(Legro et al.,

2005).
10- Hypertension
GDM risk increased among women with prehypertension and women
with hypertension during early pregnancy (Hedderson and Ferrara, 2008).
11-Iron supplementation
Iron, which is particularly abundant in the placenta, is important in the
production of free radicals. Protective mechanisms against free radical
generation and damage increase throughout pregnancy and protect the fetus,
which, however, is subjected to a degree of oxidative stress. Oxidative stress
peaks by the second trimester of, what appears to be a vulnerable period for
fetal health and gestational progress (Jiang et al., 2004).
Iron supplementation in pregnancy is beneficial for neonatal/maternal
outcomes, but it is associated with glucose impairment and hypertension in
midpregnancy; its potential harmful effects might be carefully debated
regarding its effectiveness (Bo et al., 2009).
Maternal Risks of GDM
Hyperglycemia in GDM is usually mild to affect adversely women’s

health, although there are reports of ketoacidosis (Parker and Conway, 2007)
and retinopathy (Khaldi et al., 2008).
Women with a history of GDM were more likely to have recurrent

diabetes especially if they were obese and waited longer between pregnancies
(Holmes et al., 2010).GDM is associated with a higher risk of pre-eclampsia
and metabolic syndrome (Carr et al., 2006).
26


Screening for GDM
Screening for gestational diabetes should be routine for all pregnancies

(Nicholson et al., 2005).
Screening for gestational diabetes is performed between 24 and 28 weeks

of pregnancy and may be done earlier in the pregnancy if the clinician suspects
that the woman has gestational diabetes because of risk factors such as a history
of previous GDM, obesity or a strong family history of diabetes (Dodd et al.,
2007; Simmons, 2008).
On the day of the screening test, the woman may eat and drink normally.
She will be given 50 grams of glucose, usually in the form of a specially
formulated orange or cola drink; this should be consumed within few minutes.
One hour later, a small sample of blood is drawn to measure the woman's blood
glucose level (Kim et al., 2007).
If the woman's blood glucose is elevated, further testing is needed to

determine with certainty if she has GDM. Clinicians vary in their definition of
elevated blood glucose; most consider a value greater than 126mg/dL to be
"elevated"(according to WHO). The one hour glucose test is a screening test,
meaning that not everyone who has an elevated one hour blood glucose level
will have gestational diabetes. However, if the one hour blood glucose level is
very high ≥200 mg/dL, many clinicians do not perform any further testing
because there is a very good chance that the woman has GDM (Simmons,
2008).
27


Further testing for diagnosis of GDM
The three hour (or two hour, in some locations) oral glucose tolerance test
(GTT) is used to determine with certainty if a woman has GDM. The test is
done by measuring the woman's fasting glucose level, then again one, two, and
three hours after she drinks a glucose 100 grams. A woman is said to have
GDM if her blood glucose values are above the following levels:
Fasting>95 mg/dL, 1-hour >180 mg/dL, 2-hours>155 mg/dL and 3-hours > 140
mg/dl (American Diabetic Association).
The recommended values for the diagnosis of GDM are those in (table 2)
according to Dodd et al., (2007).
28


Recommendation for diagnosis of GDM Plasma glucose level (mg/dl)
ACOG National Diabetes Data Group (USA)
-Fasting glucose 105
-One-hour post-100-g load 190
-Two-hour post-100-g load 165
-Three-hour post-100-g load 145
American Diabetes Association (USA)
-Fasting glucose 95
-One-hour post-100-g load 180
-Three-hour post-100-g load 140

WHO 1998
-Fasting glucose 126

ADIPS
-Fasting glucose 99
NZSSD
-Fasting glucose 99
ACOG=American College of Obstetricians and Gynecologists; ADIPS=

Australian Diabetes in Pregnancy Society, NZSSD= New Zealand Society for
the Study of Diabetes; WHO= World Health Organization
Table (2): Recommended values for the diagnosis of gestational diabetes

(Dodd et al., 2007).
29


Management of GDM
-Blood glucose monitoring
Women with GDM should perform home blood glucose monitoring.

Blood glucose levels are monitored in fasting state and 1–2 hours after meals.
Treatment to post-prandial targets results in superior outcomes compared to pre-
prandial targets (Jovanovic and Pettitt, 2007).
-Dietary therapy
All women should receive individualized counselling to provide

adequate calories and nutrients to meet the needs of pregnancy and consistent
with the blood glucose goals (fasting ≤105 mg/dl, 1 hr ≤155 mg/dl, and 2 hrs
≤130 mg/dl). For obese women, a 30%–33% calorie restriction to
approximately 25 kcal/kg body weight per day is recommended. Carbohydrate
should be restricted to 35%–40% of calories. Studies in which women with
GDM had less carbohydrate diet, with low glycemic index ( The glycemic index
or GI describes the ranking of carbohydrates according to their effect on our
blood glucose levels), had lower postprandial glucose levels, less likely to
require insulin, and had a lower incidence of large for gestational age newborn
(Moses et al., 2006).
-Physical activity
Women with GDM should maintain a sensible level of light and moderate
intensity physical activity, like walking for 20–30 minutes each day, and
attendance at antenatal exercise classes until the latter stages of the pregnancy.
Physical activity lowers fasting glucose levels, glucose responses to a glucose
challenge, and glycosylated hemoglobin (HbA1c), postprandial glucose levels,
and a delay in the need of insulin (Brankston et al.,2004).
30


-Insulin therapy
When treatment targets are not achieved by dietary means, then insulin is
required. Fast-acting (regular) insulin and intermediate-acting (isophane) insulin
have been the preferred insulins for the treatment of GDM. The rapid acting
insulin analogs lispro and aspart are also safe in pregnancy, and indeed, they are
commonly used (Aydin et al., 2008).
31

Chapter II Review of Literature
L

Inffants of Diabetiic Moth

hers
Diabetes is assocciated witth matern

nal and perinatal morbiditty and
mortallity. Fetaal and neeonatal mortality
m rates weere as hhigh befo
ore the
develoopment off specializzed maternal, fetaal, and neeonatal caare. Sincee then,
infantss of diabeetic motheers (IDMss) have ex
xperiencedd a decreaase in mo
orbidity
and mortality
m r
rates. Todday, 3-10%
% of preg
gnancies are
a affectted by abn
normal
glucosse regulatiion and coontrol. Off these cases, 80-88%
% is related to gesttational
diabetees mellituus. Of mothers
m xisting diabetes, 35% had type 1
wiith pre-ex
% had typee 2 diabetes mellituus (Alam eet al., 2006
diabetees mellitus, and 65% 6).
Figuree (6): Prooblems foound in IDMs

I nsient Taachypnea of the
(TTN=Tran
Newboorn; RVT
T=Renal Vein
V Throombosis) (Nold and
dGeorgiefff, 2004).
32


Problems found in Infants of Diabetic Mothers
-Altered Fetal Growth
*Macrosomia
This refers to fetal growth beyond a specific weight regardless of

gestational age, usually above 4,000 g or 4,500 g. With the development of a
national reference for fetal growth based on data from over 3.8 million births,
clinicians can distinguish between macrosomia and large-for-gestational-age
(LGA) which refers to fetal growth above the 90th percentile for a given
gestational age. Women with gestational diabetes, the mildest form of
carbohydrate intolerance, have as great an incidence of macrosomia as women
with pre-existing diabetes (Zhang et al., 2008).
Macrosomia in IDM results primarily from increased adiposity because

IDM have both adipocytes hyperplasia and adipocytes hypertrophy. IDM also
have excess non fatty tissue. The liver and heart often are enlarged, and skeletal
muscle increased. Much of this excess tissue is located in the shoulders and
intrascapular area. Because IDM have normal brain growth, this results in a
disproportion between head and shoulder size and greatly increases the risk of
shoulder dystocia (Maticot-Baptista et al., 2007).
Because insulin has both mitogenic and anabolic effects in the fetus, the
fetal hyperinsulinemic state is central to the development of macrosomia. The
effect of insulin probably is mediated to some extent through stimulation of
insulin-like growth factors. Hyperinsulinemia "primes" various tissues to the
mitogenic influence of growth factors (Thureen et al., 2006). The excess fat in
IDM develops during the third trimester; IDM delivered before 30 weeks of
gestation rarely are LGA (Grissa et al., 2007).
33


Fluctuations in glucose levels rather than basal levels are probably more
determinant in fetal growth acceleration. In diabetic pregnancies, only overall
daily glucose values < or =95 mg/dl throughout the second and third trimesters
can avoid alterations in fetal growth. These fetuses cannot be identified by a
single ultrasound examination at 29-34 weeks' gestation(Ben-Haroush et
al.,2007).Combination of sonographic estimates with clinical and demographic
variables does not improve the prediction of macrosomia at delivery in
comparison with a routine ultrasound scan within a week before delivery
(Balsyte et al., 2009).
The macrosomic offspring born to diabetic mothers are prone to the

development of glucose intolerance and obesity as a function of age. It seems
that in utero programming during diabetic pregnancy creates a "metabolic
memory" which is responsible for the development of obesity in macrosomic
offspring (Khan et al., 2007).
Macrosomia is responsible for the great risk of birth trauma, meconium

aspiration syndrome, persistent pulmonary hypertension, and high incidence of
cesarean section delivery of IDM (Dickstein et al., 2008).
*Intrauterine growth retardation
This refers to fetal growth less than or equal to the 10th percentile for
gestational age. Growth retardation in diabetic pregnancy may result from
alterations in maternal metabolic fuel availability during early gestation and it
has been attributed to maternal vascular disease, causing uteroplacental
insufficiency (Irfan et al., 2004; Howarth et al., 2007; Haeri et al., 2008).
34


-Hyperviscosity
IDM have a 10% to 20% risk of being polycythemic and developing

neonatal hyperviscosity syndrome. Several factors are responsible for this; the
hematocrit of umbilical-cord blood at birth tends to be elevated; as a result of
increased erythropoiesis. Also hyperinsulinemia results in decrease in protein C
and increases in fibrinogen factors V, VII, and XI. The increased incidence of
renal vein thrombosis reported in IDM may be related to hyperviscosity,
although this disorder does occur in IDM with normal hematocrit(Sarkar et al.,
2005).
-Cardiomyopathy
IDM are at increased risk for various cardiomyopathies. Many have

thickening of the interventricular septum and left or right ventricular wall. The
increased cardiac muscle mass results from the fetal hyperinsulinemic state.
Most of these infants are asymptomatic, and the thickening is detected by
electrocardiogram or echocardiogram. These abnormalities generally regress
over 3 to 6 months, and the condition appears to have no permanent effect on
the myocardium (Abu-Sulaiman and Subaih, 2004).
In a small fraction of infants, outflow obstruction severe enough to cause

left ventricular failure; these infants have suffered intrapartum asphyxia and are
hypoglycemic and hypocalcemic. Pregnancies of both type 1 and 2 diabetes
carry an increased risk for foetal development of pathologic ventricular
hypertrophy (PVH) compared with those with GDM (Ullmo et al., 2007).
-Congenital Abnormalities
Poor control of maternal diabetes during the first trimester, a critical

period of organogenesis, has been proposed as the mechanism for the increased
35


incidence of malformations. In his 1980 Banting Lecture, the late Norbert

Freinkel articulated the concept of “fuel-mediated teratogenesis” and pointed
out the temporal relationships between exposure to a metabolic insult and the
type of adverse effects that might ensue (Metzger, 2007). Diabetes-induced
fetal abnormalities are accompanied by some metabolic disturbances including
elevated superoxide dismutase (SOD) activity, reduced levels of myoinositol
and arachidonic acid and inhibition of the pentose phosphate shunt
pathway(Abu Sief et al., 2007;Dheen et al.,2009).
Although many abnormalities occur in IDMs, ventricular septal defects,

transposition of the great arteries, and spinal agenesis-caudal regression
syndrome occur with particular frequency. Neural tube defects, gastrointestinal
atresia, and urinary tract malformations also are relatively common (Kumar et
al., 2007; Kaissi et al., 2008).
A transient anomaly unique to IDM is known as the neonatal small left

colon, microcolon, or lazy colon syndrome. This condition presents as
gastrointestinal obstruction, and barium contrast studies suggest congenital
aganglionic megacolon.Unlike infants with Hirschsprung disease where
aganglionosis begins with the anus, which is always involved, and continues
proximally for a variable distance; these infants with small left colon syndrome
have normal innervation of the bowel and ultimately have normal bowel
function (Chen, 2005).
-Postnatal Problems
IDM are at increased risk for development of obesity and altered glucose
metabolism (impaired fasting glucose, IGT, diabetes) in the offspring in later
life, compared to infants of mothers with normal carbohydrate metabolism
(Figure 7)(Metzger, 2007). In utero hyperinsulinism may be responsible for
36

L

this phhenomenon with inttrauterine growth an

nd parentaal obesity (Schaeferr et al.,
2005).
d glucose tolerancee in offspring of diabetic

Figuree (7): Obeesity and impaired
motheers (Metzgger, 2007)).
In the passt, the incrreased incidence of birth traum

ma and neeonatal dissorders
probabbly contribbuted to an
a increassed risk off cognitive impairm
ment. An inverse
i
correlaation has been
b repoorted betw
ween childh
hood IQ and
a degreee of abnorrmality
of seccond- annd third-ttrimester maternall lipid metabolism
m m .IDMss have
impairrments in memory from
f birthh through 8 months of age thhat are con
nsistent
with allterations in mechannistic pathhways of memory
m o
observed inn animal models
m
of perrinatal iroon deficieency thatt may tarrget the developinng hippoccampus
(Siddaappa et all., 2004; Rosales
R nd Zeisel, 2008).
an
37


Gestational diabetes hinders expressive language in offspring into middle

childhood. Genes are strongly associated with the risk of delays in infants of
diabetic mothers. Genetic modeling revealed that additive genes moderate the
effect of GD on expressive language: protection or vulnerability genes are thus
strongly associated with IDMs’ expressive language skills. However, what these
genes are or do remains speculative. (Dionne et al., 2008).
Children and adults who were IDM have an increased incidence of

diabetes mellitus. It is possible that the altered metabolic state of the diabetic
pregnancy may modulate the genetic predisposition. The insulin secretory
defect could be related to low parasympathetic tone (Nold and Georgieff,
2004).
-Respiratory Distress Syndrome (RDS)
IDM are at increased risk of developing RDS. The increased risk of RDS
in poorly regulated diabetic women is due in great part to fetal hyperinsulinism,
which adversely affects fetal lung maturation by inhibiting the development of
enzymes necessary for the synthesis of the phospholipid components of
surfactant. Polycythemia is another factor with associated stagnant hypoxia. As
macrosomia is common and may cause birth injuries that may be result in
central form of respiratory distress (Barnes-Powell, 2007).
*Evaluation of the newborn's blood gas status
The transition from foetal to neonatal life is a dramatic one; it demands

considerable and effective physiological alteration in the newborn to ensure
survival. Simultaneously cardio-respiratory adjustments are initiated and
breathing maintained on a continuous basis. The basic movements in the human
foetus being about 8 weeks after conception, and by 12 weeks some of these
foetal breathing movements have attained a pattern similar to respiration. At
38


birth also, the regulatory neural network responsible for respiratory control is
capable of generating robust rhythm-driven ventilation that can adjust to
homeostatic needs. The so far unexplained conversion from episodic to
continuous breathing with the onset of birth remains one of the mysteries of
perinatal medicine. The initiation and establishment of breathing is of
paramount importance to the survival of the newborn (Arikawe and Iyawe,
2006).
Blood gas measurements are as important for ill newborn infants as for
other critically ill patients, but unique challenges are provided by rapidly
changing physiology, difficult access to arterial and mixed venous sampling
sites, and small blood volumes. Normal values for arterial blood gases are very
dependent on postnatal age. Values of PaO2 and SaO2 may also be lower in
premature infants, caused by reduced lung function (Blickstein and Green,
2007).
-Assessment of oxygenation
Blood gas measurements and noninvasive estimations provide important

information about oxygenation. Oxygen delivery (DO2) to tissues is the product
of cardiac output (c.o.) and blood oxygen content (CaO2), DO2 = c.o. x CaO2.
Ignoring the negligible oxygen dissolved in plasma, the equation can be
expanded to DO2 = (HR x SV) x (SaO2 x 1.34 x Hgb), where HR = heart rate,
SV = stroke volume, SaO2 = hemoglobin saturation, and Hb = hemoglobin
content. Insufficient oxygen delivery to tissues, hypoxia, can therefore be
caused by cardiac failure (decreased HR and (or) SV leading to decreased c.o.),
or by low hemoglobin (anemia) or low Sao2 (hypoxemia) leading to low
CaO2.When insufficient oxygen is provided to tissues, hypoxia leads to
metabolic acidosis (Brouillette and Waxman,1997). A sensor for combined
assessment of pulse oximetry oxygen saturation (Spo2) and transcutaneous
39


measurement of Pco2 (Ptcco2) has been introduced in a single ear sensor

(Bernet-Buettiker et al., 2005).
The general goals of oxygen therapy in the neonate are to maintain

adequate PaO2 and SaO2, and to minimize cardiac work and the work of
breathing .Optimal oxygenation will result in different PaO2/SaO2 goals for
different types of neonatal patients. Most commonly, premature infants in
respiratory failure should have PaO2 values between 50–80 mm Hg; these goals
minimize the chances of blindness caused by retinopathy of prematurity and
lower the inspired O2 and airway pressure requirements that, if higher, might
increase the risk of bronchopulmonary dysplasia (Walsh et al., 2009).
-Assessment of alveolar ventilation
Arterial blood gas determinations of PCO2 provide the most accurate

determinations of the adequacy of alveolar ventilation. The PaCO2
concentration reflects the balance between metabolic production of CO2 and
excretion by ventilation. There is acceptable range for PaCO2 for a given
patient. Although the normal range of PaCO2 after the first hours of life can be
considered (35–45 mm Hg), desirable CO2 values for a specific situation may
be higher or lower (Sankar et al., 2008).
-Assessment of acid–base status
Blood gases provide essential information on acid–base status both in

critically ill neonates and in chronically or less severely ill patients. One can
approach the analysis of simple acid–base disorders by answering three
questions. First, is the condition one of acidosis or alkalosis (is the pH less than
or greater than 7.4)? Second, is the primary cause metabolic (is bicarbonate high
or low) or respiratory (is PCO2 high or low)? Third, is the compensation
appropriate? (Victory et al., 2004).
40


Glucose homeostasis in newborn infants
The neonate's ability to maintain glucose homeostasis is less well

developed than the older child or adult because it is in a metabolic transition
period. The abrupt switch from intrauterine life, in which glucose and metabolic
fuels are provided in a well-regulated manner, to a situation in which meals are
intermittent and which necessitates regulation of exogenous glucose and
production of endogenous glucose. As the capability to perform these functions
continues to develop in the neonate, clinical disorders that can afflict the
neonate may perturb this balance, resulting in hypoglycemia or hyperglycemia
(Milcic, 2008).
-Glucose Producing and Glucose Regulatory Capabilities in the

Fetus
The development of glucose production and regulatory capabilities in the fetus

involves the following:
-Glycogen
As the third trimester progresses, fat deposition and hepatic glycogen

storage increase. The human fetus can synthesize and mobilize glycogen and
respond to the signals that regulate these processes as early as the ninth week of
gestation. However, only minute quantities of hepatic glycogen are present in
early gestation as the great bulk of hepatic glycogen accumulates during the
third trimester .Several types of infants are at risk for neonatal hypoglycemia as
a result of limited hepatic glycogen stores. Infants delivered prematurely have
an abbreviated or no third trimester and thus have limited glycogen stores
(Hume et al., 2005).
41


Fetuses that are growth-retarded on the basis of limited metabolic fuel

availability and diminished gaseous exchange (i.e., uteroplacental insufficiency)
will use these fuels for growth and not for glycogen synthesis. Perinatal stress
causes neonatal hypoglycemia in part because of catecholamine-stimulated
mobilization of hepatic glycogen stores (Hay, 2006).
-Gluconeogenesis
The fetus can carry out gluconeogenesis to a limited degree, although it is

likely that under normal circumstances it does not need to call on this function.
The four key gluconeogenic enzymes are present in fetal liver by 2 to 3 months
of gestation. The activities of these enzymes increase throughout gestation and
the neonatal period. Thus, all appropriately grown newborns, including the very
premature, have some degree of gluconeogenic capability (Beardsall and
Dunger, 2007).
-Endocrine Regulation
Newborn infants increase insulin and limit glucagon secretion sluggishly

in response to glucose challenge; these responses become adult-like between the
first and second weeks of life. Insulin and glucagon, important hormones for
regulating glucose, can be measured in fetal plasma as early as 12 weeks of
gestation .Although plasma concentrations of these hormones are low; the
relative content of these hormones in the fetal pancreas is quite high. Both
premature and term infants have limited secretory capacity to secrete these
hormones in response to a glucose challenge. Amino acids have a greater effect
in stimulating insulin and limiting glucagon secretion than glucose in the fetus
(Tammaro, 2007).
Insulin may be more important for enhancing growth than for regulating
metabolic fuels during fetal life. Excessive insulin secretion during fetal life
42


resulting from such conditions as IDMs causes the disproportionate growth of

insulin-sensitive tissues, and macrosomia. A lack of insulin, as in infants with
transient neonatal diabetes mellitus, always is accompanied by fetal growth
retardation (Coelho et al., 2007).
Glucagon or a critical glucagon/insulin ratio is important for inducing

gluconeogenic enzymes both vitro and in vivo. Plasma glucagon concentrations
increase progressively during fetal life, and this is associated with a concomitant
increase in gluconeogenic enzyme activity. At birth, plasma glucagon
concentrations surge, coinciding with the rapid postnatal increase in
gluconeogenic activity. However; insulin may modulate glucagon's effect
because it can inhibit gluconeogenic enzyme induction. Thus, a balance
between these two hormones controls gluconeogenic enzyme induction during
perinatal life (Hume et al., 2005).
Adrenergic mechanisms can stimulate hepatic glycogenolysis during fetal

life, much as in the adult. As labor progresses, fetal sympathoadrenal activity
increases, resulting in an increase in circulating catecholamine levels. Cord
clamping triggers an increase in glucagon secretion, as plasma glucose
concentrations drop with cord clamping, insulin secretion slowly decreases.
These adjustments, particularly the remarkable increase in catecholamine
secretion, stimulate glycogenolysis and gluconeogenesis in the neonate
(Jackson et al., 2004).
Fetal glucose metabolism depends on additive effects of fetal plasma

glucose and insulin. Glucose-stimulated insulin secretion increases over
gestation, is down-regulated by constant hyperglycemia, but enhanced by
pulsatile hyperglycemia. Insulin production is diminished in fetuses with
intrauterine growth restriction (IUGR) by inhibition of pancreatic β-cell
replication, but not by mechanisms that regulate insulin production or secretion,
43


while the opposite occurs with hypoglycemia alone, despite its common
occurrence in IUGR. Chronic hyperglycemia down-regulates glucose tolerance
and insulin sensitivity with decreased expression of skeletal muscle and hepatic
Glut 1 and 4 glucose transporters, while chronic hypoglycemia up-regulates
these transporters(Hay,2006).
Neonatal Glucose Requirements
A normal plasma glucose concentration is interpreted to mean that

glucose supply to the brain and other organs is adequate for ongoing metabolic
needs. Glucose turnover represents the rate of production of glucose by the liver
and other organs and the simultaneous use or uptake of glucose by the brain and
other organs. Turnover is usually expressed as milligrams of glucose per
kilogram of body weight per minute .In general, plasma glucose concentrations
roughly correlate with glucose turnover. Diminished plasma glucose
concentrations suggest that glucose production is limited or that glucose use is
increased. Elevated plasma glucose concentrations suggest that either
production is excessive or, more likely, organ uptake and use are diminished.
These are the dynamic physiologic conditions that define hypoglycemia and
hyperglycemia (Kapoor et al., 2009).
Neonatal Hypoglycaemia
The incidence of hypoglycaemia varies with the category of fetal growth

and the nursery feeding protocols. Early feeding decreases the incidence,
whereas prematurity, hypothermia, hypoxia, maternal diabetes, maternal
glucose infusion in labor, and intrauterine growth restriction (IUGR) increase
the incidence of hypoglycemia. Serum glucose levels decline after birth until 1–
3 hr of age, when levels spontaneously increase in normal infants (Uchigata,
2006).
44


Hypoglycaemia in the newborn, if not corrected, may lead to brain

damage and other perinatal risk factors, such as hypoxia, neonatal seizure that
would exacerbate hypoglycaemic brain injuries (Kapoor et al., 2009).
The clinical manifestations of inadequate glucose provision to the

neonatal brain range from no symptoms to lethargy or mild tremors to frank
convulsions. The issue of potential long-term sequelae is complicated by the
fact that hypoglycaemia often occurs with coexisting conditions that also can
cause brain damage .Prolonged hypoglycaemia with a greater risk of brain
damage than brief hypoglycaemia, and the extent of damage is closely
correlated to the presence of seizure-like activity (Bree et al., 2009).
A variety of blood and plasma glucose concentration values based on

screening of neonates or clinical experience have been recommended as values
defining hypoglycaemia. All of these are somewhat arbitrary because they
cannot be correlated directly with glucose use rate or severity of symptoms.
Because plasma or blood glucose concentrations only roughly reflect glucose
turnover, a plasma glucose concentration less than 40 mg/dL is used to define
hypoglycaemia (Montassir et al., 2008).
Diagnosis and Treatment of Hypoglycaemia

Asymptomatic hypoglycemia: This diagnosis is made when the blood
glucose level is below the operational threshold (to be confirmed by laboratory
estimation) in the absence of clinical signs. Symptomatic hypoglycemia: This
diagnosis should be made if the criteria according to Whipple’s Triad are
satisfied: (i) Presence of signs attributable to hypoglycemia; (ii) Low blood
glucose documented by accurate, sensitive and precise methods and (iii)
Resolution of clinical signs within minutes to hours once the blood glucose
level is normalized.
45


All infants at risk for development of hypoglycaemia should undergo

frequent plasma glucose determinations during the first 4 hours of life and then
at 4-hour intervals until the risk period has passed. If an infant is feeding, blood
sampling should be done before feeding. For IDM the screening should
continue for at least 24hours (Montassir et al., 2008).
Infants who have borderline asymptomatic hypoglycaemia, who do not

have respiratory distress syndrome (RDS) or other serious disorders, and who
are capable of enteral feeding may receive either 5% dextrose solution or
formula as their initial treatment. Intravenous administration of glucose in a
quantity sufficient to meet tissue requirements is the treatment of choice for
hypoglycaemia. The administration of 10% or 15% dextrose solution at 5 to 10
mL/kg body weight, followed by a continuous infusion at 5 to 6 mg/kg body
weight/minute, will increase plasma glucose concentrations to 40 mg/dL or
greater and acutely meet tissue requirements. The maintenance rates may
require adjustment depending on the etiology of hypoglycaemia (Stanley,
2006).
Glucagon and epinephrine increase glucose production. Because both

mobilize hepatic glycogen stores, their efficacy in treating hypoglycaemia is
variable, particularly in infants with limited hepatic stores. The numerous
cardiovascular effects of epinephrine also limit its usefulness in infants. Infants
who are hypoglycaemic for prolonged periods as a result of an inability to
produce glucose can be treated with corticosteroids (hydrocortisone 5
mg/kg/day every 12 hours; prednisone 2 mg/kg/day orally). Steroids exert some
of their effects by inducing gluconeogenic enzyme activity (Pearson, 2008).
46


Calcium Homeostasis in newborn infants
Calcium (Ca) is the most abundant mineral in the body and, together with
phosphorus (P) form the major inorganic constituent of bone. The maintenance
of Ca homeostasis requires a complex interaction of hormonal and non
hormonal factors; adequate functioning of various body systems, particularly
the renal, gastrointestinal, and skeletal systems; At all ages, the total body
content of Ca and P is about 99% and 60%, respectively(Hsu and
Levine,2004).
The mechanisms to maintain mineral homeostasis in neonates are the

same as for children and adults. However, the newborn infant has a number of
unique challenges to maintain mineral homeostasis during adaptation to
extrauterine life and to continue a rapid rate of growth. These include an abrupt
discontinuation of the high rate of intrauterine accretion of Ca (approximately
120 mg/kg/day) 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. The effects of these
tissues are exaggerated in infants with heritable disorders of mineral
metabolism, such as extracellular calcium-sensing receptor (CaR) mutations
(Egbuna and Brown, 2008), and in infants who have experienced adverse
antenatal events such as maternal diabetes (Lapillonne et al., 2008).
Circulating Concentration
Serum Ca occurs in three forms: approximately 40% is bound, mainly to

albumin; approximately 10% is chelated and complexed to small molecules
such as bicarbonate, phosphate, or citrate; and approximately 50% is ionized.
Complexed and ionized Ca (iCa) is ultrafiltrable. Total Ca concentrations (tCa)
in cord sera increase with increasing gestational age. Serum tCa reaches a nadir
47


during the first 2 days after birth; thereafter, concentrations increase and
stabilize at a level generally above 80mg/L (Hsu and Levine, 2004).
Physiological Control
Calciotropic hormones, including parathyroid hormone (PTH), 1, 25

dihydroxyvitamin D (1, 25(OH) 2 D), and possibly calcitonin (CT), appear to
maintain Ca homeostasis by intermodulation of their physiologic effects on each
other and on the classic target organs: kidney, intestine, and bone (Ramasamy,
2006).
-Parathyroid Hormone (PTH)
PTH concentrations in cord blood are low and do not correlate with PTH
concentrations in maternal sera. Serum PTH concentrations increase postnatally
coincidentally with the fall in serum Ca in both term and preterm infants. The
rise in serum PTH is greater for preterm infants with hypocalcemia compared to
term infants reflecting appropriate PTH response (Lambers et al., 2006).
PTH affects on end-organ systems through its binding to specific

receptors. The type 1 PTH/PTHrP receptor has been identified in bone,
cartilage, kidney, intestine, aorta, urinary bladder, adrenal gland, brain, and
skeletal muscle. It binds equally to PTH and PTHrP. Parathyroid hormone
(PTH) and PTH-related protein activate the same receptor but can produce
divergent effects. Another PTH receptor (type 2) responds only to PTH,
although its main endogenous ligand appears to be a 39-amino-acid peptide,
hypothalamic tubular infundibular peptide. It has been found in the brain,
pancreas, and intestines (Robert et al., 2005).
The strongest and best-characterized second messenger signalling

pathway is the PTH-stimulated coupling of the type 1 PTH receptor to the
48


stimulating G protein (Gs) however, coupling of the type 1 PTH receptor to the
Gq class protein activates phospholipase C, which generates inositol
triphosphate (IP3) and diacylglycerol (DAG). These second messengers in turn
lead to stimulation of protein kinases A and C and Ca transport channels and
result in a variety of hormone-specific tissue responses (Murray et al., 2005).
PTHrP stimulates Ca ATPase in the human syncytiotrophoblast basal

plasma membrane (BM) vesicles by activating the IP (3)-DAG-PKC pathway,
that PTHrP is important in maintaining the calcium concentration gradient
across the placental barrier in the human (Rosenblatt, 2009).
PTH acts synergistically with 1, 25(OH) 2D and is the most important

regulator of extracellular Ca concentration. PTH acts directly on bone and
kidney, and indirectly on intestine. Immediate control of blood Ca is due to
PTH-induced mobilization of Ca from bone and increased renal distal tubular
reabsorption of Ca (D’Amour et al., 2006).
There is a sigmoidal type of PTH secretion in response to decreased

serum Ca, which is most pronounced when serum Ca is in the mildly
hypocalcemic range. PTH secretion is 50% of maximal at a serum iCa of about
4 mg/dL; this is considered the calcium set point for PTH secretion (Chen and
Goodman, 2004).
-Vitamin D
Vitamin D can be obtained from diet or synthesized endogenously. It

must undergo several metabolic transformations primarily in the liver and
kidney to form the physiologically most important metabolite, 1, 25(OH)2D,
which functions as a hormone in the maintenance of mineral homeostasis. Like
other steroid hormones, 1, 25 (OH) 2D functions is mediated primarily through
modulation of the cellular genome by binding to a specific nuclear receptors,
49


vitamin D receptor, a 424-amino-acid phosphoprotein for which the x-ray

crystallographic structure has been determined (Heaney, 2005).
The genomic action of 1,25(OH)2D can be preceded by more rapid non
genomic actions that occur in minutes and involve membrane-associated events
such as increased Ca transport, and PKC and mitogen-activated protein kinase
activation. This non genomic rapid increase in cytosolic Ca within seconds
occurs in various cell types from the intestine and parathyroid, osteoblasts,
myocytes, and leukemic cells. The wide distribution of the vitamin D receptor
provides a number of clinical targets for vitamin D and its analogs. The wide
distribution of CYP27B1, the enzyme required to convert circulating 25OHD to
1, 25(OH) 2D enables a number of cells to make their own 1, 25(OH) 2D3 if
circulating 25OHD levels are maintained (Bikle, 2007).
In humans, the cord-serum vitamin D concentration is very low or

undetectable; the 25-OHD concentration is directly correlated with, but is lower
than, maternal values, consistent with placental crossover of this metabolite; and
1, 25(OH)2D concentrations also are lower than maternal values, but there is no
agreement on the maternofetal relationship of this and other dihydroxylated
vitamin D metabolites .However, the placenta, like the kidney, produces 1,
25(OH)2D, making it difficult to ascertain just how much fetal 1, 25(OH)2D
results from placental crossover versus placental synthesis(Belkacemi et al.,
2005).
There is a positive correlation between maternal vitamin D status during

pregnancy and the development of hypocalcaemia (Camadoo et al.,
2007).Maternal vitamin D deficiency in early pregnancy is associated with an
elevated risk for GDM(Zhang et al., 2008).
50


-Calcitonin (CT)
CT function is mediated by binding to receptors linked to G proteins,

members of the GPCR superfamily; CT receptors (CTR) have been identified in
the central nervous system, testes, skeletal muscle, lymphocytes, and placenta.
Secretion of CT is stimulated by an increase in serum Ca and Mg concentrations
and by gastrin, glucagon, and cholecystokinin, glucocorticoid, norepinephrine,
and calcitonin gene related peptide (CGRP); secretion is suppressed by
hypocalcemia, propranolol, somatostatin, and vitamin D (Jain et al., 2008).
Hypocalcemia
Neonatal hypocalcaemia is defined as a serum tCa concentration of less

than 8 mg/dL in term infants and 7 mg/dL in preterm infants with iCa below 4.0
to 4.4 mg/dL, depending on the particular ion-selective electrode used (Cooper
and Gittoes 2008).Clinically, there are two peaks in the occurrence of neonatal
hypocalcaemia. An early form typically occurs during the first few days after
birth, with the lowest concentrations of serum Ca being reached at 24 to 48
hours of age and late neonatal hypocalcaemia that occurs toward the end of the
first week. Many neonates, particularly those with genetic defects in Ca
metabolism, may be hypocalcemic, but remain asymptomatic and undetected
during the early neonatal period. Serum Ca values are lower in ELBW infants
(Altirkawi and Rozycki, 2008).
Hypocalcemia is not uncommon in neonates receiving gentamicin

therapy, and it may occur more frequently in boys and late-preterm infants, so
monitoring of serum Ca levels should be considered when gentamicin is given >
or = 4 days (Chiruvolu et al., 2008).
51


Pathophysiology of Hypocalcaemia:
In the neonate, hypocalcaemia frequently occurs in the presence of rising

concentrations of PTH in the circulation. This represents either a relative
inadequate response of the parathyroid gland or end-organ resistance to PTH.
Resistance to pharmacologic doses of 1, 25(OH)2D, demonstrated in vitro and in
vivo in infants, may also contribute to hypocalcaemia. Serum CT concentrations
continue to increase after birth in neonates of normal and diabetic pregnancies
(Jain et al., 2008).
Complications of hypocalcaemia
Acute complications are associated with clinical manifestations, including

seizure, apnea, cyanosis and hypoxia, bradycardia, and hypotension. Therapy-
related complications, such as cardiac arrhythmia, arterial spasm, tissue
necrosis, and extravasation of Ca solution, can be avoided by continuous
electrocardiogram monitoring during Ca infusion, avoiding infusion of Ca into
the arterial line, and checking for venous patency before Ca infusion. There is
also a risk for metastatic calcification from aggressive Ca treatment in the
presence of hyperphosphatemia (Cooper and Gittoes 2008).
52


Blood Picture and IDMs
Fetal Erythropoiesis
Early hematopoietic cells originate in the yolk sac. By the eighth week of
gestation, more definitive fetal erythropoiesis is taking place in the liver. The
liver remains the primary site of erythroid production throughout the early fetal
period. By 6 months of gestation, the bone marrow becomes the principal site of
erythroid cell development. Later during gestation, a switch occurs in the type
of haemoglobin being formed, with adult haemoglobin (HbA) re-placing fetal
haemoglobin (HbF). The site of production of erythropoietin (EPO) switches
from the less sensitive hepatic to the more sensitive renal site
(Stamatoyannopoulos, 2005).
The major difference between fetal and adult erythropoiesis is in the

response to EPO. Erythropoiesis is controlled by a feedback loop involving
EPO. A decrease in erythrocyte mass is reflected by an increase in EPO, which
drives erythropoiesis to increase erythrocyte mass and diminish EPO
production. The expected correlation between EPO and measures of oxygen
delivery (e.g., haemoglobin level, mixed venous oxygen tension, and available
oxygen) can be detected in premature neonates, providing evidence that the
same feedback loop exists. The measured levels of EPO are much lower than
those of older children and adults with corresponding degrees of anemia (Palis,
2008).
The magnitude of the EPO response was lowest in the least mature infant
(27 to 31 weeks of gestation) with low EPO values in cordocentesis samples
from infants between 18 and 37 weeks of gestation. This poor EPO response
persists through the neonatal period, resulting in a reduced erythropoietic
53


stimulus and lower haemoglobin levels in premature infants (Saizou et al.,

2004).
When maternal iron stores are depleted, the levels of iron in the fetus will
also end up with reduced fetal iron stores but no change in free iron availability.
Maternal diabetes causes depletion of fetal iron stores and is associated with
higher fetal iron demands as indicated by higher serum transferrin receptors
(STfR) and their ratio to ferritin (TfR-F index) in cord blood(Verner et al.,
2007).
Hemoglobin switching
Hemoglobin synthesis proceeds in a process referred to as “hemoglobin
switching” (Stockman and Pochedly 1988). The blood of early human
embryos contains two slowly migrating haemoglobins, Gower-1 and Gower-2,
and Hb Portland, which has Hb F–like mobility. The zeta (ζ) chains of Hb
Portland and Gower-1 are structurally quite similar to α chain. Both Gower
haemoglobins contain a unique type of polypeptide chain, the epsilon (ε) chain.
Hb Gower-1 has the structure ζ2ε2, while Gower-2 has the structure α2ε2. Hb
Portland has the structure ζ2γ2. In embryos of 4–8 wk gestation, the Gower
haemoglobins predominate, but by the 3rd month they have disappeared. Hb F
contains γ polypeptide chains in place of the β chains of Hb A. Its after the 8th
gestational wk, Hb F is the predominant hemoglobin; at 24 wk gestation it
constitutes 90% of the total hemoglobin. During the 3rd trimester, a gradual
decline occurs, so that at birth Hb F averages 70% of the total. Some Hb A
(α2β2) can be detected in even the smallest embryos (Manca and Masala,
2008).
IDM shows delay in switching from production of fetal hemoglobin to
adult hemoglobin.
54

L

Figuree (8): Hem

moglobin switchingg (Stockm
man and Pochedly
P 11988).
Normal Haemooglobin Leevels
A clear definition
d of the normal
n haaemoglobiin range iis importaant for
properr evaluatioon and maanagemennt. Normall haemogllobin valuues at birtth have
been determine
d d throughh measureement of levels inn cord bloood of neewborn
infantss. Less thaan the norm
mal rangee of hemog
globin forr birthweigght and po
ostnatal
age is defined as
a anemiaa. A “physiologic” decrease in hemogglobin con
ntent is
noticedd at 8–12 wk in terrm infants (hemoglo
obin, 11 g/dL)
g and at about 6 wk in
prematture infannts (7–10 g/dL). Iff anemia is med, a proompt and careful
i confirm
searchh for the caause shoulld be initiaated (Bizzzarro et all., 2004).
55


AGE
Gestational HEMOGLOBIN HEMATO RETICULOCYTES
(weeks) (g/dL) CRIT (%) MCV (μ3) (%)
18–20(*) 11.5 ± 0.8 36 ± 3 134 ± 8.8 N/A
21–22(*) 12.3 ± 0.9 39 ± 3 130 ± 6.2 N/A
23–25(*) 12.4 ± 0.8 39 ± 2 126 ± 6.2 N/A
26–27 19.0 ± 2.5 62 ± 8 132 ± 14.4 9.6 ± 3.2
28–29 19.3 ± 1.8 60 ± 7 131 ± 13.5 7.5 ± 2.5
30–31 19.1 ± 2.2 60 ± 8 127 ± 12.7 5.8 ± 2.0
32–33 18.5 ± 2.0 60 ± 8 123 ± 15.7 5.0 ± 1.9
34–35 19.6 ± 2.1 61 ± 7 122 ± 10.0 3.9 ± 1.6
36–37 19.2 ± 1.7 64 ± 7 121 ± 12.5 4.2 ± 1.8
38–40 19.3 ± 2.2 61 ± 7 119 ± 9.4 3.2 ± 1.4
*
Based on samples collected in utero. Results expressed as mean value ± 1
standard deviation from the mean
Table (3): Normal Hemoglobin levels during fetal and neonatal period
(Bizzarro et al., 2004).
56


One factor that can significantly influence the haemoglobin level in

newborn infants is the amount of placental transfusion. At birth, blood is rapidly
transferred from the placenta to the infant, with one-fourth of the placental
transfusion occurring within 15 seconds of birth and one-half by the end of the
first minute. Delaying clamping of the umbilical cord in full-term neonates for a
minimum of 2 minutes following birth is beneficial to the newborn, extending
into infancy. Although there was an increase in polycythemia among infants in
whom cord clamping was delayed, this condition appeared to be benign
(Hutton and Hassan, 2007).
-Polycythemia
Venous haemoglobin exceeding 22 g/dL or a venous hematocrit more

than 65% during the first week of life should be regarded as polycythemia.
Although neonatal polycythemia may be the result of fetal disorders such as
twin-to-twin transfusion, placental insufficiency, and certain metabolic
disorders, most cases occur in otherwise normal infants. Most of these infants
have been full-term, appropriate for gestational age and without asphyxia at
birth (Sarkar and Rosenkrantz, 2008).
The symptoms in the polycythemic infant are due to hypervolemia and an

increase in blood viscosity. After the central venous hematocrit reaches 60% to
65%, the increase in blood viscosity becomes greater due to the exponential
relationship between hematocrit and viscosity. Respiratory distress,
thrombocytopenia, cyanosis, congestive heart failure, convulsions, priapism,
jaundice, renal vein thrombosis, hypoglycaemia, and hypocalcaemia appear to
be more common in infants with polycythemia. Many infants with
polycythemia are asymptomatic (Jeevasankar et al., 2008).
57


-Treatment of symptomatic polycythemia

Partial exchange transfusion (with normal saline). The Hct level at which
a partial exchange transfusion is indicated, in an asymptomatic infant, is unclear
but should not be considered if the Hct is ≤70–75%. Partial exchange will lower
the Hct and viscosity and improve acute symptoms (Pappas and Delaney-
Black, 2004).
The long-term prognosis of polycythemic infants is unclear. Reported

adverse outcomes include speech deficits, abnormal fine motor control, reduced
IQ, school problems, and other neurologic abnormalities. It is thought that the
underlying etiology (chronic intrauterine hypoxia) and hyperviscosity contribute
to adverse outcomes. It is unclear whether partial exchange transfusion
improves the long-term outcome. Most asymptomatic infants develop normally
(Dempsey and Barrington, 2006).
58

L

Bilirrubin Metabolism
m and ID
DMs
-Form
mation, Strructure, and
a Propeerties of Bilirubin
B
Bilirubin is the ennd producct of the catabolism

c m of hem
me, of whiich the
major source is circulatting haem
moglobin. The form
mation off bilirubin
n from
haemooglobin invvolves rem
moval of the
t iron an
nd proteinn moieties, followed
d by an
oxidatiive process catalyzzed by thhe enzymee microsoomal hemee oxygenaase, an
enzym
me found in
i the retticuloendoothelial sy
ystem andd many otther tissuees. The
methanne bridge of the heme
h porpphyrin ring
g is openned and caarbon mo
onoxide
(CO) and bilivverdin is formed .O
One moleecule of CO and biliverdin
n (and,
subseqquently, biilirubin) iss formed for
f each molecule
m of heme deegraded (F
Fevery,
2008; Ryter and
d Choi, 2009).
Figuree (9): ch
hemical structuree of natturally occurring
o g unconju
ugated
bin (Fevery, 2008)..
bilirub
59


-Fetal Bilirubin Metabolism
The major route of fetal bilirubin excretion is the placenta. Because

virtually all the fetal plasma bilirubin is unconjugated, it is readily transferred
across the placenta to the maternal circulation to be excreted by the maternal
liver. Thus, the newborn rarely is born jaundiced, except in the presence of
severe hemolysis, when there may be accumulation of unconjugated bilirubin in
the fetus. Conjugated bilirubin is not transferred across the placenta, and it may
accumulate in the fetal plasma and tissues (McDonagh, 2007).
Bilirubin can be detected in normal amniotic fluid after about 12 weeks of

gestation, but it disappears by 36 to 37 weeks' gestation. The ability of human
fetal liver to remove bilirubin from the circulation and to conjugate it is severely
limited. Between 17 and 30 weeks of gestation, uridine diphosphoglucuronosyl
transferase (UDPGT) activity in fetal liver is only 0.1% of adult values, but it
increases tenfold to 1% of adult values between 30 and 40 weeks' gestation.
After birth, activity increases, reaching adult levels by 6 to 14 weeks' gestation
(Macias et al., 2009).
Neonatal Bilirubin Metabolism
-Bilirubin Production
The normal destruction of circulating erythrocytes accounts for about

75% of the daily bilirubin production in the newborn. Senescent erythrocytes
are removed and destroyed in the reticuloendothelial system, where the heme is
catabolized and converted to bilirubin (Maisels and Kring, 2006).
-Transport and Hepatic Uptake of Bilirubin
Once bilirubin leaves the reticuloendothelial system, it is transported in

the plasma and bound reversibly to albumin. When the bilirubin-albumin
60


complex reaches the plasma membrane of the hepatocyte, a proportion of the

bilirubin, but not the albumin, is transferred across the cell membrane into the
hepatocyte, a process that involves four different transport proteins. In the
hepatocyte, bilirubin is bound principally to ligandin and possibly other
cytosolic-binding proteins. A network of intracellular microsomal membranes
plays an important role in transfer of bilirubin within the cell and to the
endoplasmic reticulum (Reiser, 2004).
-Conjugation and Excretion of Bilirubin
Unconjugated bilirubin is nonpolar and insoluble in aqueous solutions at

pH 7.4 and must be converted to its water-soluble conjugate before it can be
excreted. This is achieved when bilirubin is combined enzymatically with
glucuronic acid, producing bilirubin monoglucuronide and diglucuronide
pigments that are more water soluble and sufficiently polar to be excreted into
the bile or filtered through the kidney (Chen et al., 2005).
The process of conjugation is catalyzed by glucuronoyl transferase which

is synthesized in the hepatocyte, a specific enzyme A1 isoform (UGT1A1)
belonging to the uridine diphosphoglucuronate glucuronosyltransferase (UGT)
family of enzymes (Costa, 2006).
-Physiologic Mechanisms of Neonatal Jaundice
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 enterohepatic circulation. An imbalance between bilirubin production and
conjugation is fundamental in the pathogenesis of neonatal hyperbilirubinemia
(Reiser, 2004).
61


A-Increased Bilirubin Load on the Liver Cell
1-Increased Bilirubin Production
CO is produced in equimolar quantities with bilirubin and measurements

of CO production show that the normal newborn produces an average of 8 to 10
mg/kg of bilirubin per day. This is more than twice the rate of normal daily
bilirubin production in the adult and is explained by the fact that the neonate has
a higher circulating erythrocyte volume, a shorter mean erythrocyte lifespan,
and a larger early bilirubin peak. Bilirubin production decreases with increasing
postnatal age but is still about twice the adult rate by age 2 weeks (Newman et
al., 2005).
2-Increased Enterohepatic Circulation
The newborn reabsorbs larger quantities of unconjugated bilirubin by

way of the enterohepatic circulation, than the adult. Infants have fewer bacteria
in the small and large bowel and greater activity of the deconjugating enzyme
b-glucuronidase .As a result, conjugated bilirubin, which is not reabsorbed, is
not converted to urobilinogen but is hydrolyzed to unconjugated bilirubin,
which is reabsorbed, and increasing the bilirubin load on an already stressed
liver. In the first few days after birth, caloric intake is low, which contributes to
an increase in the enterohepatic circulation (Tiribelli and Ostrow, 2005).
B-Decreased Clearance of Bilirubin from the Plasma
1-Impaired Uptake
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. And
62


administration of Phenobarbital increases the concentration of ligandin; this

suggests that impaired uptake may contribute to the pathogenesis of physiologic
jaundice (Rigato et al., 2005).
2-Impaired Conjugation
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 the first 10 days after
birth, UGT1A1 activity in full-term and premature neonates usually is less than
1% of adult values then, the activity increases at an exponential rate, reaching
adult values by 6 to 14 weeks of age, that increase in UGT1A1 activity is
independent of the infant's gestation(Wang et al., 2006).
3-Limited Excretion
The absence of an elevated serum level of conjugated bilirubin in

physiologic jaundice suggests that, under normal circumstances, the neonatal
liver cell is capable of excreting the bilirubin that it has just conjugated.
However, the ability of the newborn liver to excrete conjugated bilirubin and
other anions (e.g., drugs, hormones) is more limited than that of the older child
or adult and may become rate limiting when the bilirubin load is significantly
increased. Thus, when intrauterine hyperbilirubinemia occurs, usually as a result
of isoimmunisation, it is not uncommon to find an elevated serum level of
conjugated bilirubin (Fevery, 2008).
63

Subjects and Methods

This study was carried on 40 neonates their gestational age ranged from 32-41
weeks.
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 Abu Alreish hospital and NICU of
Obstetric hospital within Al Kasr Al Aini in the period from August 2008 to
August 2009.They were 10 males and 30 females .
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 pregestational diabetes (n=20)
Group III: IDMs whose mothers had gestational diabetes mellitus. (n=20)
In group II (IDMs whose mothers had pregestational diabetes) respiratory

distress (RD) was the commonest cause of admission in this group, followed by
hypoglycemia and jaundice in addition to heart failure. The congenital
anomalies appeared in this group affected five of the patients and were in the
form of cardiomegaly, tricuspid regurge (TR), mitral regurge (MR), and
pulmonary regurge (PR).
64


In group III (IDMs whose mothers had gestational diabetes), also the
most common complication to maternal diabetes in this group is respiratory
distress in addition to hypoglycemia, jaundice and hypoxic ischemic
encephalopathy. The congenital anomalies appeared in this group affected
five patients of group III and were in the form of bone and joint anomalies,
hydrocephalus, menngomyelocele, renal cyst, left ventricular hypertrophy,
septal hypertrophy and patent ductus arteriosus (PDA).
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- Complete Blood Count (CBC) with differential leucocytic count.
4- Serum bilirubin level.
5- Arterial Blood Gases (ABG).
6-Acid base status (HCO3, pH and BE/BD).
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 after
birth.
65

d Methods
Subjects and

-Meth
hodologyy:
The gesttational age

a assesssed by New Baallard scoore (NBS
S), for
neurom
muscular maturity
m a physiccal maturiity and it was provided in neeonates
and
files. The
T exam
mination coonsists off six neuro
omuscularr criteria aand six ph
hysical
criteriaa. The neuuromuscullar criteriaa are based on the understand
u ding that passive
p
tone iss more useeful than active
a tonee in indicaating gestaational agee. The agreeement
n Gabriel et al.,
betweeen two obbservers inn NBS asssessment was donne (Marín
2006). It slightlly overesttimates thhe GA witth increassing postnnatal age (PNA).
(
Neurollogical signs are more
m reliaable than physical ones (Sassidharan et al.,
2009).
Fig (1):
( NewB
Ballard Sccore (Marrín Gabriiel et al., 22006)
66


Measurements were obtained through automated systems. We measured

Serum glucose, calcium, bilirubin by (Beckman Coulter Hmx-analyzer,
Fullerton, CA).Complete Blood Picture for anticoagulated blood samples
(EDTA in the collecting tubes) were measured by Sysmex KX-21N, America,
Inc. ABG was measured by GASTAT-602i Blood gas system.
67


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)
SD= d
n −1
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
68


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.
Correlation
Correlation was done to show the association between two quantitive variables.
It is described from two main parameters:
(1) The strength:
It is expressed as a number that ranges between 0 in case of absence and 1 in
case of perfect correlation.
(2)The direction:
It is expressed either as positive or negative. The positive correlation means that
as the values of one variable increase, the value of the other variable increase
too. The negative correlation means that as the values of one variable decrease,
the value of the other variable increase, i.e. Inverse relation (Knapp and
Miller, 1992).
69


All statistical calculations were done using computer programs Microsoft Excel
2003 (Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the
Social Science; SPSS Inc., Chicago, IL, USA) version 17 for Microsoft
Windows.
70

Results

Results
A-Descriptive statistics
Table (1): Shows mean ±standard deviation (SD) of the measured variables among studied groups
Group IIa Group IIb Group IIIa Group IIIb
Parameter Control(n=20) (n=20) (n=20) (n=20) (n=20)
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
PH 7.39±.028 7.24±.156 7.38±.045 7.31±.133 7.41±.083
PO2(mm Hg) 88.06±5.263 47.71±22.368 89.28±4.322 63.79±25.185 90.32±16.482
PCO2(mm Hg) 40.14±3.093 52.69±19.187 38.50±3.744 42.97±24.030 36.29±13.367
HCO3(mEq/L) 21.35±2.067 22.00±4.677 22.71±2.795 19.15±5.284 22.91±3.429
BE/BD(mEq/L) -1.16±.644 -3.82±6.742 -1.68±2.376 -5.97±5.116 -2.08±2.060
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
71

Results

Hb(g/dL) 16.71±2.495 17.12±3.828 16.31±3.224 14.49±4.719 14.08±3.288
RBCs(million/cmm) 5.34±.846 5.27±.968 5.07±.774 4.40±1.097 4.35±.865
PCV (%) 53.09±7.168 52.45±11.807 50.83±10.780 45.54±13.936 43.72±11.179
MCV(fL) 105.53±6.673 96.83±9.567 94.91±9.224 97.63±10.801 97.26±10.589
MCH(pg) 35.10±2.872 33.35±3.699 33.48±3.448 32.17±4.121 32.18±3.524
MCHC(g/dL) 35.22±2.768 34.40±2.427 34.45±2.669 32.90±3.102 32.96±2.506
RDW (%) 16.08±2.994 18.94±5.213 18.39±4.290 20.13±3.916 18.95±3.499
Retics(%) 1.43±.892 3.11±2.566 2.91±2.360 2.41±1.280 2.31±1.051
WBC(1000/cmm) 17.85±6.144 15.36±6.063 15.73±6.407 16.88±8.253 15.34±6.615
Staff (%) 3.30±3.063 7.35±5.314 6.10±5.973 9.65±7.358 5.55±5.652
Segmented (%) 55.50±6.613 48.00±10.926 48.00±10.214 49.05±10.211 52.90±11.652
Platelets(1000/cmm) 332.75±88.859 244.90±113.973 237.85±112.657 181.55±106.119 222.25±135.704

TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin. RBCs=Red Blood Corpuscles, Hb=Hemoglobin, PCV=Packed Cell Volume,
MCV=Mean Corpuscular Volume, MCH=Mean Corpuscular Hemoglobin, MCHC= Mean Corpuscular Hemoglobin Concentration, RDW=Red
Cell Distribution Width, WBC=White Blood Cells.
72

Results

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)
Pairs t Sig. (2-tailed)
Glucose2 - Glucose1 6.551 .000*
Calcium2 - Calcium1 4.577 .000*
* P<0.05= significant
In group II There was a significant increase (P value < 0.05) in pH in
before discharge (7.38±.045) compared to values on admission
(7.24±.156).Also, there was a significant increase (P value < 0.05) in PO2
values before discharge (89.28±4.322mmHg) compared to values on admission
(47.71±22.368) mm Hg.
There was a significant decrease (P value < 0.05) in PCO2 values before
discharge (38.50±3.744 mm Hg) compared to values on admission
(52.69±19.187 mm Hg).
73

Results

There was no statistically significant difference between, HCO3 levels

before discharge (22.71±2.795 mEq/L) to values measured on admission
(22.00±4.677 mEq/L).Also there was no significant difference in BE/BD
measurements before discharge (-1.68±2.376 mEq/L) compared to those on
admission(-3.82±6.742 mEq/L).
Table (3) Paired sample test for Arterial blood gas analysis components at
admission and before discharge (Group II).
PH2 - PH1 4.515 .000*
PO2. 2 - PO2. 1 8.109 .000*
PCO2. 2 - PCO2. 1 -3.168 .005*
HCO3.2 - HCO3. 1 .635 .533
BE/BD 2 - BE/BD 1 1.374 .185
*P<0.05=Significant
-As revealed from table (4)
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/dl).
Table (4) Paired sample test for total and direct bilirubin at admission and
before discharge (Group II)
TSB2 - TSB1 -1.243 .229
DSB2 - DSB1 -1.002 .329
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
74

Results


In group II there was a significant decrease (P value < 0.05) in
hemoglobin value measured before discharge (16.31±3.224gm/dl) compared to
value on admission (17.12±3.828gm/dl).There was a significant decrease (P
value < 0.05) in RBCs count before discharge (5.07±.774 million/cmm)
compared to count on admission (5.27±.968 million/cmm).Other variables of
complete blood counts (CBC) didn’t show significant difference in values
before discharge compared to the values measured on admission.
Table (5) Paired sample test for Complete Blood Count at admission and
before discharge (Group II).
Hb2 - Hb1 -2.406 .026*
RBCs2 - RBCs1 -2.164 .043*
PCV2 - PCV1 -1.765 .094
MCV2 - MCV1 -1.548 .138
MCH2 - MCH1 .443 .663
MCHC2 - MCHC1 .201 .843
RDW2 - RDW1 -1.070 .298
Retics.2 - Retics.1 -1.313 .205
TLC2 - TLC1 .367 .718
staff.2 - staff.1 -.974 .342
segmen.2 - segmen.1 .000 1.000
Lymph.2 - Lymph.1 -.299 .768
Basophil2 - Basophils1 -1.277 .217
esinophils2 - esinophils1 -.279 .783
PLT.2 - PLT.1 -.516 .612
*P<0.05=Significant
RBCs=Red Blood Corpuscles, Hb=Hemoglobin, PCV=Packed Cell Volume,
MCV=Mean Corpuscular Volume, MCH=Mean Corpuscular Hemoglobin, MCHC= Mean
Corpuscular Hemoglobin Concentration, RDW=Red Cell Distribution Width,
WBC=White Blood Cells.
75

Results

-Group III (IDMs whose mothers had gestational diabetes)
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 (6) Paired sample test for serum glucose and calcium at admission
and before discharge (Group III).

Glucose2 - Glucose1 2.275 .035*
Calcium2 - Calcium1 7.850 .000*
*P<0.05=Significant
In group III There was a significant increase (P value < 0.05) in pH in
before discharge (7.41±.083) compared to values on admission
(7.31±.133).Also, there was a significant increase (P value < 0.05) in PO2
values before discharge (90.32±16.482mmHg) compared to values on
admission (63.79±25.185 mm Hg).There was no statistically significant
difference in PCO2 values before discharge (36.29±13.367mm Hg) compared to
values on admission (42.97±24.030mm Hg).
Both HCO3 and BE/BD levels were significantly increased (P value <
0.05) in measurements before discharge compared to those on admission
(22.91±3.429 mEq/L versus 19.15±5.284 mEq/L and -2.08±2.060 mEq/L versus
-5.97±5.116 mEq/L respectively).
76

Results

Table (7) Paired sample test for Arterial blood gas analysis components at
admission and before discharge (Group III).
Pairs T Sig. (2-tailed)
PH2 - PH1 3.086 0.006*
PO2. 2 - PO2. 1 4.163 0.001*
PCO2. 2 - PCO2. 1 1.041 0.311
HCO3.2 - HCO3. 1 3.253 0.004*
BE/BD 2 - BE/BD 1 3.255 0.004*
*P<0.05= significant
-As revealed from table (8)
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 (8) Paired sample test for total and direct bilirubin at admission and
before discharge (Group III).
TSB2 - TSB1 .877 .392
DSB2 - DSB1 .895 .382
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
In group III there was a significant decrease (P value < 0.05) in RDW in
measurement before discharge (18.95±3.499%) compared to those on admission
(20.13±3.916%).
There was a significant decrease in staff PMNL count in values measured
before discharge (5.55±5.652%) as compared to those on admission
(9.65±7.358%). Other variables of complete blood counts (CBC) didn’t show
77

Results

significant difference in values before discharge compared to the values

measured on admission.
Table (9) Paired sample test for Complete Blood Count at admission and
before discharge (Group III).
Hb2 - Hb1 -1.253 .226
RBCs2 - RBCs1 -.419 .680
PCV2 - PCV1 -1.639 .118
MCV2 - MCV1 -.723 .479
MCH2 - MCH1 .050 .961
MCHC2 - MCHC1 .269 .791
RDW2 - RDW1 -2.855 .010*
Retics.2 - Retics.1 -1.169 .257
TLC2 - TLC1 -1.257 .224
staff.2 - staff.1 -5.626 .000*
segmen.2 - segmen.1 1.660 .113
Lymph.2 - Lymph.1 .000 1.000
Basophil2 - Basophils1 .736 .471
esinophils2 - esinophils1 -1.000 .330
PLT.2 - PLT.1 -.326 .748
*P<0.05=Significant
Hb=Hemoglobin, RBCs=Red Blood Corpuscles, PCV=Packed Cell Volume, MCV=Mean
Corpuscular Volume, MCH=Mean Corpuscular Hemoglobin, MCHC= Mean Corpuscular
Hemoglobin Concentration, RDW=Red Cell Distribution Width, WBC=White Blood Cells.
78

Results

2-Analysis of Variance (ANOVA) test
-Comparison between variables on admission in group II and group III and

control group:
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) (Figure
1).
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 groupIII (7.34±1.203 mg/dl) on
admission compared to control group (9.80±.894 mg/dl) (Figure 2).
Table (10) Comparison of serum glucose and calcium in group II, group III
on admission and control group.
Measured variable Control Group IIa Group IIIa P-value

(n=20) (n=20) (n=20)
Glucose (mg/dl) 84.25±14.414 49.95±20.493 65.45±41.140 0.000*
Calcium (mg/d)l 9.80±.894 7.68±1.348 7.34±1.203 0.000*
There was a significant decrease in pH (P value < 0.05) in group II

(7.24±.156) and group III on admission (7.31±.133) compared to control group
(7.39±.028) (Figure14).
A significant decrease (P value < 0.05) in PO2 in group II (47.71±22.368

mmHg) and groupIII on admission (63.79±25.185 mmHg) compared to control
group (88.06±5.263mmHg) as shown in (Figure11).On the opposite side a
79

Results

significant increase (P value < 0.05) was revealed in PCO2 in group II

(52.69±19.187mmHg) and group III on admission (42.97±24.030mmHg)
compared to control group (40.14±3.093mmHg) (Figure 12).
There was no significant difference in HCO3 values between group II

(22.00±4.677mEq/L) and group III on admission (19.15±5.284 mEq/L) and
control group (21.35±2.067mEq/L), (Figure13).
BE/BD was significantly decreased (P value < 0.05) both in group II (-

3.82±6.742 mEq/L) and groupIII on admission (-5.97±5.116 mEq/L) compared
to control group (-1.16±.644 mEq/L) (Figure15).
Table (11) Comparison of Arterial Blood Gas analysis in group II, group
III on admission and control group.
Measured Control Group IIa Group IIIa P-value

Parameter (n=20) (n=20) (n=20)
PH 7.39±.028 7.24±.156 7.31±.133 0.000*
PO2(mm Hg) 88.06±5.263 47.71±22.368 63.79±25.185 0.000*
PCO2(mm Hg) 40.14±3.093 52.69±19.187 42.97±24.030 0.006*
HCO3(mEq/L) 21.35±2.067 22.00±4.677 19.15±5.284 0.101
BE/BD(mEq/L) -1.16±.644 -3.82±6.742 -5.97±5.116 0.001*
There was a significant increase (P value < 0.05) in TSB in group II

(9.80±5.807 mg/dl) and groupIII 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±2.857
mg/dl) and groupIII on admission (0.56±0.239 mg/dl) compared to control
group (0.80±0.433 mg/dl) (Figure 4).
80

Results

Table (12) Comparison of total and direct serum bilirubin in group II,
group III on admission and control group.

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
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin
There was a significant decrease (P value < 0.05) in RBCs count in group
II (5.27±.968million/cmm) and groupIII on admission (4.40±1.097
million/cmm) compared to control group (5.34±.846 million/cmm).
There was a significant decrease in blood indices (MCV, MCH, MCHC)

in group II and groupIII on admission compared to control group.
There was also a significant increase (P value < 0.05) in RDW in group II
(18.94±5.213%) and groupIII on admission (20.13±3.916%) compared to
control group (16.08±2.994%) (Figure10).
A significant increase (P value < 0.05) in retics was observed in group II

(3.11±2.566%) and group III on admission (2.41±1.280%) in comparison to
control group (1.43±.892%).
There was a significant increase (P value < 0.05) in staff PMNL count in
group II (7.35±5.314%) and groupIII on admission (9.65±7.358%) compared to
control group (3.30±3.063%) (Figure8).While there was a significant decrease
(P value < 0.05) in segmented count in group II (48.00±10.926%) and group III
on admission (49.05±10.211%) compared to control group (55.50±6.613%).
81

Results

There was a significant decrease (P value < 0.05) in platelets count in

group II (244.90±113.973 x 1000/cmm) and group III (181.55±106.119 x
1000/cmm) on admission compared to control group (332.75±88.859 x
1000/cmm) (Figure 9).
Table (13) Comparison of Complete Blood Count in group II, group III on
admission and control group.
Hb(gm/dl) 16.71±2.495 17.12±3.828 14.49±4.719 0.195
RBCs(million/cmm) 5.34±.846 5.27±.968 4.40±1.097 0.011*
PCV (%) 53.09±7.168 52.45±11.807 45.54±13.936 0.118
MCV(fL) 105.53±6.673 96.83±9.567 97.63±10.801 0.009*
MCH(pg) 35.10±2.872 33.35±3.699 32.17±4.121 0.056*
MCHC(g/dl) 35.22±2.768 34.40±2.427 32.90±3.102 0.018*
RDW (%) 16.08±2.994 18.94±5.213 20.13±3.916 0.011*
Retics (%) 1.43±.892 3.11±2.566 2.41±1.280 0.037*
TLC(1000/cmm) 17.85±6.144 15.36±6.063 16.88±8.253 0.389
Staff (%) 3.30±3.063 7.35±5.314 9.65±7.358 0.003*
Segmented (%) 55.50±6.613 48.00±10.926 49.05±10.211 0.047*
Lymph (%) 26.25±9.227 29.90±11.544 26.15±8.689 0.491
Mon (%) 9.90±5.590 9.35±5.631 10.20±5.197 0.863
Basophils (%) .95±.887 1.25±.967 1.05±.999 0.641
Esinophils (%) 4.10±2.075 4.15±2.254 3.80±1.989 0.860
Platelets(1000/cmm) 332.75±88.85 244.90±113.973 181.55±106.119 0.000*
9
*P<0.05=Significant
Hb=Hemoglobin, RBCs=Red Blood Corpuscles, PCV=Packed Cell Volume, MCV=Mean
Corpuscular Volume, MCH=Mean Corpuscular Hemoglobin, MCHC= Mean Corpuscular
Hemoglobin Concentration, RDW=Red Cell Distribution Width, WBC=White Blood Cells.
82

Results

-Comparison between variables before discharge in group II and group III

and control group:
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 groupIII (8.71±1.173mg/dl) before
discharge relative to control group (9.80±.894 mg/dl) (Figure 2).
Table (14) Comparison of serum glucose and calcium in, group II, group
III before discharge and control group.
Measured Control Group IIb Group IIIb P-value

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*
There was a significant increase (P value < 0.05) in HCO3 values in

group II (22.71±2.795 mEq/L) and group III (22.91±3.429mEq/L) before
discharge compared to control group (21.35±2.067mEq/L) (Figure13). Other
variables measured in ABG didn’t show statistically significant difference in
group II and group III before discharge compared to control group.
83

Results

Table (15) Comparison of Arterial Blood Gas analysis in group II, group
III before discharge and control group.
Measured Control Group IIb Group IIIb p-value

PH 7.39±.028 7.38±.045 7.41±.083 0.835
PO2(mm Hg) 88.06±5.263 89.28±4.322 90.32±16.482 0.853
PCO2(mm Hg) 40.14±3.093 38.50±3.744 36.29±13.367 0.452
HCO3(mEq/L) 21.35±2.067 22.71±2.795 22.91±3.429 0.026*
BE/BD(mEq/L) -1.16±.644 -1.68±2.376 -2.08±2.060 0.501
*P<0.05=Significant
There was a significant increase (P value < 0.05) in TSB in group II

(7.89±4.197mg/dl) and groupIII (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±.446
mg/dl) and groupIII (0.64±.343 mg/dl) before discharge compared to control
group (0.80±.433 mg/dl) (Figure 4).
Table (16) Comparison of total and direct serum bilirubin in group II,

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
84

Results

There was a significant decrease (P value < 0.05) in Hb level in group II

(16.31±3.224 gm/dl) and groupIII (14.08±3.288 gm/dl) before discharge in
comparison to control group (16.71±2.495 gm/dl).
There was a significant decrease (P value < 0.05) in RBCs count in group
II (5.07±.774 million/cmm) and groupIII (4.35±.865 million/cmm) before
discharge compared to control group (5.34±.846 million/cmm).
A significant decrease (P value < 0.05) in PCV in group II

(50.83±10.780%) and groupIII (43.72±11.179%) before discharge as compared
to control group (53.09±7.168%) (Figure 6).
There was a significant decrease in blood indices (MCV, MCH, MCHC)

in group II and groupIII before discharge compared to control group.
A significant increase (P value < 0.05) in retics was observed in group II

(2.91±2.360%) and group III (2.31±1.051%) before discharge in comparison to
control group (1.43±.892%).
There was a significant decrease (P value < 0.05) in platelets count in

group II (237.85±112.657 x1000/cmm) and group III (222.25±135.704
1000/cmm) before discharge as compared to control group (332.75±88.859
1000/cmm) (Figure9).
85

Results

Table (17) Comparison of Complete Blood Count in, group II, group III
before discharge and control group.

Hb(gm/dl) 16.71±2.495 16.31±3.224 14.08±3.288 0.032*
RBCs(million/cmm) 5.34±.846 5.07±.774 4.35±.865 0.002*
PCV (%) 53.09±7.168 50.83±10.780 43.72±11.179 0.024*

MCV(fL) 105.53±6.673 94.91±9.224 97.26±10.589 0.002*
MCH(pg) 35.10±2.872 33.48±3.448 32.18±3.524 0.025*
MCHC(gm/dl) 35.22±2.768 34.45±2.669 32.96±2.506 0.027*
RDW (%) 16.08±2.994 18.39±4.290 18.95±3.499 0.069
Retics.(%) 1.43±.892 2.91±2.360 2.31±1.051 0.027*
TLC(1000/cmm) 17.85±6.144 15.73±6.407 15.34±6.615 0.364
Staff (%) 3.30±3.063 6.10±5.973 5.55±5.652 0.395
Segmented (%) 55.50±6.613 48.00±10.214 52.90±11.652 0.075
Lymph (%) 26.25±9.227 29.45±11.067 26.15±9.885 0.571
Mon (%) 9.90±5.590 11.60±5.968 11.00±4.611 0.573
Basophils(%) .95±.887 .90±1.021 .80±.834 0.877
Esinophils(%) 4.10±2.075 3.95±2.665 3.60±1.984 0.729
Platelets(1000/cmm) 332.75±88.859 237.85±112.657 222.25±135.704 0.002*
*P<0.05=Significant
RBCs=Red Blood Corpuscles PCV=Packed Cell Volume, Hb=Hemoglobin,
MCV=Mean Corpuscular Volume, MCH=Mean Corpuscular Hemoglobin, MCHC= Mean
Corpuscular Hemoglobin Concentration, RDW=Red Cell Distribution Width, WBC=White
Blood Cells,
86

Results

mg/dl
Glucose
e
1
120
G
GroupA
A*
1
100 88.15
84.25 84.25
80
65.45
60 49.95
40
20
0
control groupIIa groupIIb groupIIIa groupIIIb
Group
*significant P as compaared to contrrol
Figuree (1) Com

mparison of
o serum glucose leevel (mg/d
dl) amongg the stud
died
groups
Calciium
mg//dl Grou
upA*andd Group
p B*
12
9.8
10 8.71
8.59
7.675 7.335
8
0
b
Group
*signifiicant P as coompared to control
Figuree (2): Com

mparison of serum
m calcium level (mgg/dl) amon
ng the stu
udied
groups
87

Results

TSB
B
mg/dl
2
20
GroupA* and
d Group
pB*
1
15
9.795
1
10 7.89 5.81 6.818
5 2.79
0 control groupIIa groupIIb groupIIIa groupIIIb

Group
Figuree (3): Com

mparison of serum
m total biliirubin (mg/dl) leveel among the
t
studieed groups

mg/d
dl DSSB
5
2 1.4
417
0.805 0.74
425 0.64
4
1 0.5
56
0
control grroupIIa grroupIIb gro
oupIIIa grroupIIIb
‐1 Gro
oup
‐2
Figuree (4): Com

mparison of serum
m level of direct
d biliirubin (mg/dl) amo
ong
the stu
udied group
88

Results

ggm/d
Hb
2
l
25
G
GroupB*
*
2
20 16.95263158 17.115 16.31
4.48947368
14 14.075
1
15
1
10
0
Group
Figuree (5): Com

mparison of hemogglobin lev
vel amongg the studiied group
p
PCV
%
7
70
Group B*
6
60 53.09 52.45 50.83
5
50 45.54 43.72
4
40
3
30
2
20
1
10
0
*signifficant P as comparedd to controol
Figuree (6): Com

mparison of packed
d cell volu
ume (%) among th
he studied
d
group
89

Results

10000/cmm TLC
30
25
20 17.85 16.875
15.36 15.73 1
15.335
15
10
0
control groupIIa groupIIb groupIIIaa groupIIIb
Group
Figuree (7): Com

mparison of total leeucocytic count am
mong the sstudied grroup
Staff
%
2
20
GroupAA*
1
15
9.65
1
10 7.35
6.1 5.55
5 3.3
0
b
Group
‐
‐5
Figuree (8): Com

mparison of staff. Count
C am
mong the studied
s grroup
90

Results

10000/cmm
Platele
ets
5
500
Group
pA* andd GroupB*
4
400 332.75
3
300 244.9 237.85 222.25
181.55
2
200
1
100
0
b
Group
Figuree (9): Com

mparison of plateleets countss among the
t studied group
RDWW
%
3
30
GroupA
A*
2
25
18.94 20.125 18.95
2
20 18.39
16.085
1
15
1
10
5
0
Group
Figuree (10): Coomparison

n of red cell
c distrib
bution wid
dth amon
ng the stud
died
group
91

Results

PO2
2
m
mmHg
GroupA*
120
100 88.06 89.275 90.315
80
63.79
60 47.715
40
20
0
Group

n of oxygeen tension
n (mm Hgg) among the studiied
group
mmHg Pco2
80
G
GroupA *
60 52.685
40.145 42.97
38.495 36.285
40
20
n of carboon dioxide tension among th

Figuree (12): Coomparison he studied
d
group
92

Results

mEq/L HCO3
3
30
G
GroupB *
2
25 22 22.71 22.91
21.345
19.15
2
20
1
15
1
10
5
0 control groupIIa groupIIb groupIIIa groupIIIb
Group

n of bicarrbonate leevel amon
ng the stud
died grou
ups
pH
GrroupA*
7.6
7.5
7.391 7.3845 7.4065
7.4
7.306315789
7.3 7
7.23635
7.2
7.1
7
6.9
6.8
control grroupIIa groupIIb g
groupIIIa groupIIIb
Group
n of pH among thee studied group

Figuree (14): Coomparison g
93

Results

4 BE//BD
2
Grou
up A*
0
‐2 ‐1.16
‐1.68
‐2.085
‐4
‐3.82
‐6
‐5.965
b
‐8
BE/BD 1
n of base deficit/ex
Figuree (15): Coomparison xcess among the stu
udied group
94

Results

C-Correlations
1-Correlation between serum glucose level (mg/dl) and total serum
bilirubin level (mg/dl) bilirubin:
A- Correlation between serum glucose level TSB in control group (groupI):
Table (18): No significant correlation between serum glucose levels TSB in

control group (group I)
Glucose TSB
Glucose Pearson Correlation 1 .416
Sig. (2-tailed) .068
TSB Pearson Correlation .416 1
Figure (16): No significant correlation between serum glucose level TSB in

control group (group I)
95

Results

B- Correlation between serum glucose (mg/dl) levels TSB (mg/dl) in group II

on admission (group IIa):
Table(19): A significant positive correlation between serum glucose level

and total serum bilirubin in group II on admission
Glucose1 TSB1
Glucose1 Pearson Correlation 1 .463*
TSB1 Pearson Correlation .463* 1
Figure (17): A significant positive correlation between serum glucose level

and total serum bilirubin in group II on admission
96

Results

C- Correlation between serum glucose (mg/dl) levels TSB (mg/dl) in groupIII

on admission (groupIII a)
Table (20): No significant correlation between serum glucose (mg/dl) levels

and TSB (mg/dl) in groupIII on admission (groupIII a)
Glucose1 TSB1
Glucose1 Pearson Correlation 1 -.120
TSB1 Pearson Correlation -.120 1
Figure (18): No significant correlation between serum glucose (mg/dl) levels

and TSB (mg/dl) in groupIII on admission (group IIIa)
97

Results

2-Correlation between gestational age and total leucocytic count

A- Correlation between gestational age and total leucocytic count in control
group (group I):
Table (21): No significant correlation between gestational age and total

leucocytic count in control group (group I)
GA(WKs) TLC
GA(WKs) Pearson Correlation 1 .023
TLC Pearson Correlation .023 1
Figure (19): No significant correlation between gestational age and total

leucocytic count in control group (Group I)
98

Results

B- Correlation between gestational age and total leucocytic count group II on

admission (group IIa)

leucocytic count group II on admission (group IIa)
GA(WKs) TLC1
TLC1 Pearson Correlation .008 1

leucocytic count in group II on admission (group IIa)
99

Results

C-Correlation between gestational age and total leucocytic count in groupIII

on admission (group IIIa)

GA(WKs) TLC1
TLC1 Pearson Correlation .022 1

100

Results

3-Correlations between staff count and gestational age:

A- Correlations between staff count and gestational age in control group
(group I)
Table (24): No significant correlation between staff count and gestational

age in control group (group I)
GA(WKs) staff
staff. Pearson Correlation .145 1
Figure (22): No significant correlation between staff count and gestational

age in control group (group I)
101

Results

B-Correlations between staff count and gestational age in group II on


age in group II on admission (group IIa)
GA(WKs) staff.1
staff.1 Pearson Correlation .033 1

age in group II on admission (group IIa)
102

Results

C-Correlations between staff count and gestational age in groupIII on

admission (group IIIa)

age in groupIII on admission (group IIIa)
GA(WKs) staff.1
N 20 20
staff.1 Pearson Correlation .032 1
N 20 20

age in groupIII on admission (group IIIa)
103

Results

4-Correlation between reticulocytic index and gestational age

A-Correlation between Reticulocytic index and gestational age in control
group (group I)
Table (27) No significant correlation between reticulocytic index and

RETICULOCYT
GA(WKs) E INDEX
RETICULOCYTE INDEX Pearson Correlation .227 1
Figure (25): No significant correlation between reticulocytic index and

104

Results

B-Correlation between Reticulocytic index and gestational age in group II on

Table (28): A significant positive correlation between reticulocytic index

RETICULOCYT
GA(WKs) E INDEX
GA(WKs) Pearson Correlation 1 .504*
RETICULOCYTE INDEX Pearson Correlation .504* 1
*. Correlation is significant at the 0.05 level (2-tailed).
Figure (26): A significant positive correlation between Reticulocytic index

105

Results

C- Correlation between reticulocytic index and gestational age in groupIII on

admission (group IIIa)
Table (29): No significant correlation between reticulocytic index and

RETICULOCYT
GA(WKs) E INDEX
RETICULOCYTE INDEX Pearson Correlation .105 1
Figure (27): No significant correlation between reticulocytic index and

106

Results

5-Correlations between total serum bilirubin and gestational age

A- Correlations between total serum bilirubin and gestational age in control
group (group I)
Table (30): No significant correlation between total serum bilirubin and

GA(WKs) TSB
TSB Pearson Correlation .058 1
Figure (28): No significant correlation between total serum bilirubin and

107

Results

B- Correlations between total serum bilirubin and gestational age in group II

on admission (group IIa)

GA(WKs) TSB1
GA(WKs) Pearson Correlation 1 -.026

108

Results

C- Correlations between total serum bilirubin and gestational age in groupIII

on admission (group IIIa)

GA(WKs) TSB1
GA(WKs) Pearson Correlation 1 -.134

109

Discussion

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 (Walkinshaw, 2005).
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 (Platt et al., 2002).
The present study tried to investigate the effect of maternal diabetes (both
gestational and pregestational diabetes) on some hematological and biochemical
parameters of their offspring, and the effect of treatment and admission in
NICU on these parameters.
Serum glucose level, serum calcium, serum bilirubin (both total and
direct bilirubin levels), complete blood count (CBC), arterial blood gases
(ABG) were determined in 60 newborn infants , fulfilled the criteria for the
study and classified into 3groups:
Group I (control group) which contained twenty healthy neonates.
Group II which contained twenty infants of diabetic mothers whose mothers
had pregestational diabetes (both type I and type II).
Group III which contained twenty infants of diabetic mothers whose mothers
had gestational diabetes mellitus.
Both group II and III are infants admitted to NICU due to any outcome of
maternal diabetes and the variables under investigation were measured twice,
on admission (group IIa ,group IIIa) and before discharge (group IIb ,group
IIIb).For control group measurements were performed once just after birth.
110

Discussion

In the present study, serum glucose level significantly increased in the

same group before discharge than on admission; in group II (84.25±16.049
mg/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 10,
figure1), with no significant difference between serum glucose in group II and
group III before discharge and control group (table 14, figure1).
There was a significant positive correlation in group II on admission

between serum glucose level (mg/dl) and total serum bilirubin level (mg/dl)
(table 19, figure 17).
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
hypoglycaemia. 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 (Persson, 2009).
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 hypinsulinism theory. Mothers with the highest
111

Discussion

fasting glucose had infants with the highest frequency of clinical neonatal
hypoglycaemia (Persson, 2009).
Vela-Huerta et al., (2008) 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) who demonstrated raised cord insulin and leptin concentrations
in offspring of mothers with type 2 diabetes and GDM.
Maayan-Metzger et al., (2009) demonstrated that infants born to

diabetic mothers 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 2
hours of life (Van Howe and Storms, 2006).
In the current study serum calcium levels were significantly increased in

the same group before discharge than on admission in group II (8.59±1.002
mg/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 10,14; figure2).
Hypocalcaemia is a common problem among IDMs during the neonatal

period. This usually occurs in association with hyperphosphatemia and
occasionally with hypomagnesemia (Barnes-Powell, 2007).
112

Discussion

Banerjee et al. (2003) 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 alpha subunits of
heterotrimeric G-proteins with consequent hypoparathyroidism, causing
neonatal hypocalcaemia (Quitterer et al., 2001).
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 (Bond et al., 2005).
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 (Alam et al. 2006).
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, and
hypoalbuminemia leading to decreased total but normal ionized calcium
(Lapillonne et al., 2008).
Also, there may be diminished end-organ responsiveness to hormonal

regulation of mineral homeostasis, although the functional capacity of the gut
113

Discussion

and kidney improves rapidly within days after birth (Egbuna and Brown,
2008).
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±2.857
mg/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,
figure 4). 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±1.261
mg/dl) (table 12,16; figure 3) .
There was no significant difference in DSB between group II and

groupIII neither on admission nor before discharge and the control group
(0.80±.433 mg/dl), as shown in (table 15, 19; figure 4).
Moreover, there was no significant correlation between TSB and

gestational age in group II , group III on admission and control group ,as shown
in (tables 30, 31, 32; figures 28, 29, 30).
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 enterohepatic circulation. An imbalance between bilirubin production and
conjugation is fundamental in the pathogenesis of neonatal hyperbilirubinemia
(Reiser, 2004).
114

Discussion

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 (Wang et al., 2006).
In contrast to the current study Jaber, (2006) 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 (Michael Weindling, 2009). 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 colonisation
resulting in further enhancement of bilirubin enterohepatic circulation
(Cashore, 2000). 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
(Rigato et al., 2005).
Moreover; polycythemia frequently occurs in IDM, and the normal

breakdown of this increased erythrocyte mass also causes hyperbilirubinemia
(Pappas and Delaney-Black, 2004). There is increased haemoglobin
breakdown and bilirubin production. The increased rate of erythrocyte
breakdown in IDM may be linked to altered erythrocyte membrane composition
that results from changes in maternal fuel availability (Winkler et al., 2008).
115

Discussion

In the present work, group II showed a significant decrease in RBCs

count before discharge compared to RBCs count on admission (5.07±.774
million/cmm before discharge and5.27±.968 million/cmm on admission);
however there was no significant difference in RBCs count within group III
before discharge compared to RBCs count on admission (4.35±.865
million/cmm before discharge and 4.40±1.097 million/cmm on admission).
There was significant decrease in RBCs count in group II and group III
both on admission and before discharge compared to control group (5.34±.846
million/cmm) (table13) (table 17)
In the present study, in group II there was a significant decrease in

hemoglobin before discharge compared to level on admission (16.31±3.224
gm/dl before discharge and 17.12±3.828 gm/dl on admission), however in
group III there was no significant difference in hemoglobin value before
discharge compared to that measured on admission (14.08±3.288 gm/dl before
discharge and 14.49±4.719 gm/dl on admission).
Although there was no significant difference in Hb between group II and

group III on admission and the control group (16.71±2.495 gm/dl)(table 13,
figure 5), there was significant decrease in Hb in group II and group III before
discharge compared to control group as shown in (table 17, figure 5).
In the present study there was no significant difference in PCV within

the same group before discharge compared to values on admission neither in
group II (50.83±10.780% before discharge and 52.45±11.807% on admission),
nor in group III (43.72±11.179% before discharge and 45.54±13.936% on
admission).
116

Discussion

There was no significant difference in PCV in group II and group III on

admission compared to control group (53.09±7.168%) (table 13; figure 6),
however there was significant decrease in PCV in group II and group III before
discharge compared to control group (table 17; figure 6).
Several factors may contribute to polycythemia observed in group II .

Insulin itself may promote erythropoiesis. Insulin, at levels found in IDMs, can
stimulate growth of late erythroid progenitors in tissue culture. There is an
inverse changes of circulating fetal insulin like growth factor 1 ( IGF-1) and
insulin like growth factor binding protein-1 (IGFBP-1 ) at birth with decrease
in circulating IGFBP-1 and an increase in circulating IGF-1(Lindsay et al.,
2007).
IGF-1 stimulates Hypoxia-inducible factor (HIF)-1 transcription and
translation (Slomiany and Rosenzweig, 2007).HIF-1 and HIF-2 are
heterodimeric transcription factors permits the activation of genes essential to
cellular adaptation to low oxygen conditions including the vascular endothelial
growth factor (VEGF), erythropoietin and glucose transporter-1(Déry et al.,
2005).
Although under basal conditions the fetal kidneys are the main site of
erythropoietin (EPO) production, during hypoxia there is an important role of
the placenta. Teramo and Widness, (2009) reported that amniotic fluid EPO
levels have been shown to increase exponentially during fetal hypoxia in
diabetic pregnancies.
Tissue hypoxia is the major stimulus of EPO synthesis in fetuses and
adults. Since EPO does not cross the placenta and is not stored, fetal plasma and
amniotic fluid levels indicate EPO synthesis and elimination. Acutely, the rate
and magnitude of the increase in plasma EPO levels correlate with the intensity
of hypoxia.
117

Discussion

In fetuses of diabetic mothers, hypoxia is the result of an increased

affinity of oxygen for glycosylated hemoglobin in the mother. The
hyperglycaemic environment also results in erythroblastosis in the fetus which
is accompanied by a delay in the switch from embryonic to fetal hemoglobin
chain production (Al- Mufti et al., 2004).
However ,Pappas and Delaney-Black, (2004) found that polycythemia

does not correlate with higher maternal hemoglobin A1 concentration or with
increased infant weight percentile, but it correlates with neonatal
hypoglycaemia .
During periods of hypoxia, the fetus is reliant on the activation of a

growth-driving cascade, the hypoxia-inducible factor (HIF) cascade. The
upregulation of HIF in hypoxic conditions leads to expression of genes
encoding vascular endothelial growth factor, thus increasing vascularization, as
well as erythropoietin, to increase red blood cell production for the transport of
oxygen. It also results in increased expression of glucose transporters and
glycolytic enzymes. Unfortunately in the hypoxic condition of fetuses of
diabetic mothers, glucose is already present, in abundance. This hyperglycemia,
which initially is enhanced by HIF, causes a negative feedback of the hypoxia
inducible factor cascade by degrading HIF (Lampl & Jeanty, 2004). Thus, the
fetus is faced with a conundrum due to the overly abundant glucose availability
and inevitable hypoxia. Consequences of hypoxia include increasing the level of
glucose available for neurons, with glucose signalling its own sufficiency, thus
prematurely turning the adaptive mechanisms off, and starving the body and
brain of oxygen (Lampl & Jeanty, 2004).
Axelsson et al., (2005) showed that leptin level may be a predictor of

EPO sensitivity. The effect could be either direct stimulation of erythropoiesis
or indirect stimulation by associated adipokines.
118

Discussion

Atègbo et al., (2006) demonstrated that GDM is linked to the down-

regulation of adiponectin and up-regulation of leptin and inflammatory
cytokines.
In the present work there was no significant difference in MCV,MCH and

MCHC within the same group before discharge compared to values on
admission neither in group II (table 5 ), nor in group III (table 9).
There was significant decrease in MCV, MCH and MCHC in group II

and group III both on admission and before discharge compared to control
group (tables 13, 17).
In the present study there was no significant difference in retics within the
same group before discharge compared to values on admission neither within
group II (2.91±2.360% before discharge and 3.11±2.566% on admission) nor
group III (2.31±1.051% before discharge and 2.41±1.280% on admission).
There was significant increase in retics in group II and group III both on
admission and before discharge compared to control group (1.43±.892%)
(tables 13, 17).
There was a significant positive correlation between reticulocytic index

and gestational age in group II on admission (table 28, figure 26).
Ervasti et al., (2008) found a positive correlations between EPO and the
percentage of hypochromic red blood cells and reticulocytes. Thus, in newborn
cord blood, the higher number of red cells and reticulocytes with lower Hb
content may have impaired the oxygen carrying capacity that has been a trigger
for EPO production. Furthermore, signs of lower hemoglobinization of red cells
are associated with low umbilical vein pH in the newborns, indicating an
increased risk of birth asphyxia.
119

Discussion

In the present study, although there was no significant difference in RDW

within the same group before discharge compared to values on admission in
group II (18.39±4.290% before discharge and 18.94±5.213%on admission),
there was a significant decrease in RDW within groupIII before discharge
compared to values on admission (18.95±3.499% before discharge and
20.13±3.916% on admission)
There was a significant increase in RDW in group II and group III on

admission compared to control group (16.08±2.994%) (table 13, figure 10),
however there was no significant difference in RDW in group II ,group III
before discharge, and control group (table 17; figure 10).
Red cell distribution width is a quantitative measure of anisocytosis, the

variability in size of the circulating erythrocytes. It is routinely measured by
automated haematology analyzers and is reported as a component of the
complete blood count. Red cell distribution width is typically elevated in
conditions of ineffective red cell production (such as iron deficiency, B12 or
folate deficiency, and hemoglobinopathies), increased red cell destruction (such
as hemolysis), or after blood transfusion. Conceivably, RDW may represent an
integrative measure of multiple pathologic processes in heart failure (e.g.,
nutritional deficiencies, renal dysfunction, hepatic congestion, inflammatory
stress), explaining its association with clinical outcomes (Ozkalemkas et al.,
2005).
In a study by Felker et al., (2007) RDW was found to be a very strong

marker associated with heart failure pathophysiology. Red cell distribution
width also may be related to other known markers of prognosis in heart failure,
such as inflammatory cytokines. Inflammatory cytokines have been shown to be
predictors of prognosis in heart failure, and also may impact bone marrow
function and iron metabolism . Proinflammatory cytokines have been found to
120

Discussion

inhibit erythropoietin-induced erythrocyte maturation, which is reflected in part

by an increase in RDW. Future studies that carefully evaluate RDW in the
context of more complete evaluation of iron metabolism and markers of
inflammation in heart failure patients may provide further insight into the
mechanisms of the interaction between the hematologic and cardiovascular
systems.
In the present study there was no significant difference in TLC within the
same group before discharge compared to count on admission neither in group
II (table 5) nor in group III (table 9).
There was no significant difference in TLC between group II and group III
neither on admission nor before discharge as compared to control group (tables
13, 17; figure 7).
No significant correlation was found between total leucocytic counts and

gestational age in group II, groupIII and control group; on admission (tables 21,
22, 23; figures 19, 20, 21).
In the present work, group II showed no significant difference in staff

PMNL count before discharge compared to count on admission
(6.10±5.973%before discharge and 7.35±5.314 %on admission), while in group
III there was significant decrease in staff PMNL count before discharge
compared to count on admission (5.55±5.652% before discharge and
9.65±7.358% on admission).
There was significant increase in staff in group II and group III on

admission compared to control group (table 13; figure 8) with no significant
difference in staff PMNL count between the studied groups before discharge
(table 17; figure 8).
121

Discussion

No significant correlation was found in group II, group III on admission

and control group between staff PMNL and gestational age (tables 24, 25, 26;
figures 22, 23, 24).
In the present study there was no significant difference in segmented

PMNL count within the same group before discharge compared to count on
admission neither within group II (48.00±10.214% before discharge and
48.00±10.926% on admission), nor within group III (52.90±11.652% before
discharge and 49.05±10.211% on admission).
There was significant decrease in segmented PMNL count in group II and

group III on admission compared to control(55.50±6.613%)(table 13 ),
however there was no significant difference in segmented PMNL count between
group II , group III before discharge and control (table 17 ).
Mimouni et al., (1986) demonstrated a significant "shift to the left” in

IDM's-LGA only. The usual cause of "shift to the left" such as maternal
hypertension or fever, respiratory distress syndrome, meconium aspiration,
neonatal asphyxia, sepsis, convulsions, or hypoglycemia could not explain this
finding. It is hypothesized that increased glucocorticoid secretion may possibly
play a role.
Mehta and Petrova,(2005) studied neutrophil functions in neonates

born to gestational diabetic mothers and concluded the impairment of cord
blood neutrophil motility and postphagocytic bactericidal capacity
independently from the insulin requirements for the maintenance of
normoglycemia during pregnancy.
In the present study there was no significant difference in platelets count

within the same group before discharge compared to count on admission
neither in group II (237.85±112.657X1000/cmm)before discharge and
122

Discussion

244.90±113.973 X1000/cmm on admission), nor group III (222.25±135.704

X1000/cmm before discharge and 181.55±106.119 X1000/cmm on admission).
There was significant decrease in platelets count in group II and group III
on admission and before discharge as compared to control (332.75±88.859
X1000/cmm), (table13; figure 9) (table 17; figure 9).
30% of patients in group III had anemia , shift to the left with toxic
granulation and thrombocytopenia.
Green et al., (1995), demonstrated that that in IDMs, increased

erythropoiesis is accompanied by decreased platelet counts. These data are
consistent with the theory of an erythropoietin-induced shift of fetal multipotent
stem cell differentiation toward erythropoiesis at the expense of thrombopoiesis.
In the present work there was a significant increase in PO2 within the
same group before discharge compared to value on admission both within
group II (89.28±4.322 mm Hg before discharge and 47.71±22.368 mm Hg on
admission) and group III (90.32±16.482 mm Hg before discharge and
63.79±25.185 mm Hg on admission).
There was a significant decrease in PO2 in group II and group III on

admission compared to control group (88.06±5.263 mm Hg), (table 11; figure
11), however there was no significant difference in PO2 between group II and
group III before discharge and control group(table 15; figure 11).
The low PO2 values in IDMs may be due to high incidence of

prematurity with reduced pulmonary functions or may be due to increased
incidence of RDS in premature IDMs.
123

Discussion

In the present work; group II showed a significant decrease in

PCO2within the same group before discharge compared to values on admission
(38.50±3.744 mm Hg before discharge and 52.69±19.187 mm Hg on
admission), however in group III there was no significant difference in PCO2
before discharge and on admission (36.29±13.367 mm Hg before discharge
and 42.97±24.030 mm Hg on admission).
There was significant increase in PCO2 in group II and group III on

admission as compared to control group (40.14±3.093 mm Hg) (table 11; figure
12). No significant difference in PCO2 between group II and group III before
discharge and control group (table 15; figure 12).
In the present study group II showed no significant difference in

HCO3within the same group before discharge compared to value on admission
(22.71±2.795 mEq/L before discharge and 22.00±4.677 mEq/L on admission).
In group III, there was significant increase in HCO3 within the same group
before discharge as compared to values on admission (22.91±3.429 mEq/L
before discharge and 19.15±5.284 mEq/L on admission).
There was no significant difference in HCO3 between group II and group

III on admission and control (21.35±2.067 mEq/L) (table 11), however there
was a significant increase in HCO3 in group II, group III before discharge and
control group (table 15; figure 13).
In the present work there was significant increase in pH within the same
group before discharge compared to values on admission both within group II
(7.38±.045 before discharge and 7.24±.156on admission) and within group III
(7.41±.083 before discharge and 7.31±.133 on admission).
There was a significant decrease in pH between group II and group III on

admission and control group(7.39±.028) (table 11), however there was no
124

Discussion

significant difference in pH between group II and group III before discharge and
control group (table 15).
In the present work group II showed no significant difference in BE/BD

within the same group before discharge compared to levels on admission (-
1.68±2.376 mEq/L before discharge and -3.82±6.742 mEq/L on admission) but
in group III there was significant increase in BE/BD within the same group
before discharge compared to values on admission (-2.08±2.060 mEq/L before
discharge and -5.97±5.116 mEq/L on admission).
There was a significant increase in BE/BD in group II and group III on

admission compared to control group (-1.16±.644 mEq/L) (table 11, figure
15).No significant difference in BE/BD between group II group III before
discharge and control group (table 15, figure 15).
The changes in acid base status is of respiratory type (respiratory
acidosis).This could be contributed to the fact that infants of diabetic mothers
are more likely to have respiratory symptoms in the newborn period from either
RDS (surfactant deficiency) or retained fetal lung fluid (transient tachypnea of
the newborn) especially after operative delivery (Barnes-Powell, 2007).
RDS occurs more frequently in IDMs (Infants of Diabetic Mothers)
because of later onset of maturity of the type II alveolar cells (Schumacher et
al., 2006) and is secondary to pulmonary surfactant deficiency. Fetal
hyperinsulinism is a key factor in the pathogenesis of RDS because insulin is
believed to antagonize the physiological maturing effect of cortisol.
Hyperinsulinism is also responsible for polycythemia, a condition inducing
persistent pulmonary hypertension which complicates the course of RDS (Nold
and Georgieff, 2007).
125

Summary and Conclusion

Summary and Conclusions
Diabetes mellitus during pregnancy increases fetal and maternal

morbidity and mortality. 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, hypoglycaemia, adverse neurodevelopment outcomes,
congenital anomalies, hypocalcaemia, hypomagnesaemia, and iron
abnormalities.
We conducted this study aiming to investigate the effect of maternal

diabetes on some hematological and biochemical parameters of their offspring
and the reversibility of changes in these parameters with admission to neonatal
intensive care unit(NICU).The study was carried on 60 neonates, their
gestational age ranged from 32-41 weeks. They were classified into three
groups:
Group I (control group): this group included 20 apparently healthy neonates,

their mothers are healthy, and have no diabetes or history of serious diseases.
Group II: this group included 20 IDMs from mothers with pregestational
diabetes (both type I and type II) and admitted to NICU for any complication of
maternal diabetes.
Group III: this group included 20 IDMs from mothers with gestational diabetes
and admitted to NICU for any complication of maternal diabetes.
For all subjects, serum glucose level, serum calcium level, total serum
bilirubin, direct serum bilirubin, arterial blood gases and complete blood count
were 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.
126


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. There was a significant
positive correlation in group II on admission between serum glucose level
(mg/dl) and total serum bilirubin level (mg/dl).
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 groupIII neither on admission nor
before discharge and the control group. Moreover, there was no significant
correlation between TSB and gestational age in control group, group II group
III on admission.
In group II there was a significant decrease in hemoglobin before

discharge compared to level on admission, however in group III there was no
significant difference in hemoglobin value before discharge compared to that
measured on admission. Although there was no significant difference in Hb
between group II and group III on admission and the control group, there was
127


significant decrease in Hb in group II and group III before discharge compared

to control group.
There was no significant difference in PCV within the same group before
discharge compared to values on admission neither in group II, nor in group
III.There was no significant difference in PCV in group II on admission
compared to control group, however there was significant decrease in PCV
between group II and group III before discharge compared to control group.
No significant difference was observed in MCV, MCH and MCHC

within the same group before discharge compared to values on admission
neither in group II, nor in group III.There was significant decrease in MCV,
MCH and MCHC in group II and group III both on admission and before
discharge compared to control group.
There was no significant difference in retics within the same group before
discharge compared to values on admission neither within group II nor group
III.There was significant increase in retics in group II and group III both on
admission and before discharge compared to control group. There was a
significant positive correlation between reticulocytic index and gestational age
in group II on admission.
Although there was no significant difference in RDW within the same

group before discharge compared to values on admission in group II, there was
a significant decrease in RDW within groupIII before discharge compared to
values on admission .There was a significant increase in RDW in group II and
group III on admission compared to control group, however there was no
significant difference in RDW in group II ,group III before discharge, and
control group .
Group II showed no significant difference in staff PMNL count before

discharge compared to count on admission, while in group III there was
128


significant decrease in staff PMNL count before discharge compared to count

on admission. There was significant increase in staff in group II and group III
on admission compared to controls group with no significant difference in staff
PMNL count between the studied groups before discharge. No significant
correlation was found in group II, group III on admission and control group
between staff PMNL and gestational age.
There was no significant difference in platelets count within the same

group before discharge compared to count on admission neither in group II, nor
group III. There was significant decrease in platelets count in group II and
group III on admission and before discharge as compared to control.
Arterial blood gases measurements revealed that in IDMs the changes in

acid base status is of respiratory type (respiratory acidosis) with compensatory
increase in HCO3 levels.
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.
Polycythemia in group II of IDMs as compared to control was decreased

with discharge. The increase in reticulocytic index and the decrease in blood
indices persisted even before discharge.
RDW which indicates anisocytosis was more prolonged in group II than

group III.
129


The increase in staff PMNL count was improved while the decrease in
platelets count persisted even before discharge.
Recommendations:
1-Early diagnosis of hypoglycemia and hypocalcaemia is lifesaving and should

be expected in IDMs.
2-Respiratory complications in IDMs are reversible by proper and rapid

interference.
3-Further studies are recommended to investigate the required duration needed

for parameters that did not improve on admission and reversed back to normal.
4- RDW and its association with heart failure pathophysiology may be used as a
predictor for IDMs selection for having echocardiography.
130

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‫اﻟﻤﻠﺨﺺ اﻟﻌﺮﺑﻰ‬
‫ان اﻻﺻﺎﺑﺔ ﺑﻤﺮض اﻟﺴﻜﺮى اﺛﻨﺎء اﻟﺤﻤﻞ ﻳﺰﻳﺪ ﻣﻌﺪﻻت اﻻﻋﺘﻼل واﻟﻮﻓﻴﺎت ﻟﻜﻞ ﻣﻦ اﻻم و اﻟﻄﻔﻞ‪ .‬اﻃﻔﺎل‬
‫اﻻﻣﻬﺎت اﻟﻤﺮﻳﻀﺎت ﺑﺎﻟﺴﻜﺮى ﻳﻜﻮﻧﻮن اآﺜﺮ ﻋﺮﺿﻪ ﻟﻼﺻﺎﺑﺔ ﺑﺼﻌﻮﺑﺔ ﻓﻰ اﻟﺘﻨﻔﺲ‪,‬ﻧﻤﻮ ﻏﻴﺮ ﻃﺒﻴﻌﻰ‪,‬زﻳﺎدة‬
‫ﻓﻰ ﻟﺰوﺟﺔ اﻟﺪم‪,‬زﻳﺎدة ﻓﻰ ﻧﺴﺒﺔ اﻟﺒﻴﻠﻴﺮوﺑﻴﻦ‪,‬ﻧﻘﺺ ﻓﻰ ﺗﺮآﻴﺰ اﻟﺴﻜﺮ ﺑﺎﻟﺪم ‪ ,‬ﻧﺘﺎﺋﺞ ﺳﻠﺒﻴﺔ ﻋﻠﻰ اﻟﻨﻤﻮ اﻟﻌﺼﺒﻲ‬
‫‪,‬ﻋﻴﻮب ﺧﻠﻘﻴﺔ‪,‬ﻧﻘﺺ ﻓﻰ ﺗﺮآﻴﺰ اﻟﻜﺎﻟﺴﻴﻮم و اﻟﻤﺎ ﻏﻨﺴﻴﻮم ﺑﺎﻟﺪم‪,‬و ﺗﺸﻮهﺎت اﻟﻘﻠﺐ واﻷوﻋﻴﺔ اﻟﺪﻣﻮﻳﺔ‪.‬‬
‫ﻓﻲ هﺬا اﻟﺒﺤﺚ ﺗﻢ دراﺳﺔ ﺗﺎﺛﻴﺮ اﺻﺎﺑﺔ اﻻم ﺑﻤﺮض اﻟﺴﻜﺮى ﻋﻠﻰ ﺣﺪوث ﺑﻌﺾ اﻟﺘﻐﻴﺮات اﻟﺘﻰ ﺗﺤﺪث ﻓﻰ‬
‫ﻋﻨﺎﺻﺮ اﻟﺪم و آﺬﻟﻚ ﺗﺮآﻴﺰ اﻟﻌﻨﺎﺻﺮ اﻟﻜﻴﻤﻴﺎﺋﻴﺔاﻟﻤﺬاﺑﺔ ﻓﻰ اﻟﺒﻼزﻣﺎ ﻟﺪى اﺑﻨﺎﺋﻬﻦ و ﺗﺄﺛﻴﺮ اﻟﻌﻼج ﺑﻮﺣﺪة‬
‫اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻟﻼﻃﻔﺎل ﺣﺪﻳﺜﻰ اﻟﻮﻻدة ﻋﻠﻰ هﺬﻩ اﻟﺘﻐﻴﺮات‪.‬‬
‫ﺗﻢ اﺟﺮاء اﻟﺒﺤﺚ ﻋﻠﻰ ﺳﺘﻴﻦ ﻃﻔﻞ ﺣﺪﻳﺚ اﻟﻮﻻدة‪ ,‬اﻟﻌﻤﺮ اﻟﺤﻤﻠﻲ ﻟﻬﻢ ﻳﺘﺮاوح ﻣﻦ ‪ 32‬اﻟﻰ ‪ 41‬اﺳﺒﻮع ‪,‬ﺗﻢ‬
‫ﺗﻘﺴﻴﻤﻬﻢ اﻟﻰ ﺛﻼﺛﺔ ﻣﺠﻤﻮﻋﺎت‪:‬‬
‫اﻟﻤﺠﻤﻮﻋﺔ اﻻوﻟﻰ‪):‬اﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ(‪:‬و ﺗﺘﻜﻮن ﻣﻦ ﻋﺸﺮﻳﻦ ﻃﻔﻞ ﻃﺒﻴﻌﻲ وﻻ ﺗﻌﺎﻧﻰ اﻣﻬﺎﺗﻬﻦ ﻣﻦ اى‬
‫اﻣﺮاض ﻗﺒﻞ او اﺛﻨﺎء اﻟﺤﻤﻞ‪.‬‬
‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ‪ :‬ﺗﺘﻜﻮن ﻣﻦ ﻋﺸﺮﻳﻦ ﻃﻔﻞ اﻣﻬﺎﺗﻬﻦ ﻣﺼﺎﺑﺎت ﺑﻤﺮض اﻟﺴﻜﺮى ﻗﺒﻞ ﺣﺪوث اﻟﺤﻤﻞ)آﻼ‬
‫اﻟﻨﻮﻋﻴﻦ ‪,‬اﻻول و اﻟﺜﺎﻧﻰ(‪.‬‬
‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻟﺜﺔ‪ :‬ﺗﺘﻜﻮن ﻣﻦ ﻋﺸﺮﻳﻦ ﻃﻔﻞ اﻣﻬﺎﺗﻬﻦ اﺻﺒﻦ ﺑﻤﺮض اﻟﺴﻜﺮى اﺛﻨﺎء اﻟﺤﻤﻞ‪.‬‬
‫ﻓﻰ اﻟﺜﻼث ﻣﺠﻤﻮﻋﺎت ﺗﻢ ﻗﻴﺎس ﻣﺴﺘﻮى اﻟﺠﻠﻮآﻮزواﻟﻜﺎﻟﺴﻴﻮم و اﻟﺒﻴﻠﻴﺮوﺑﻴﻨﻮ اﻟﺒﻴﻜﺮﺑﻮﻧﺎت ﺑﺎﻟﺪم ﻣﻊ ﻋﻤﻞ‬
‫ﺻﻮرة دم آﺎﻣﻠﺔ و ﻗﻴﺎس اﻟﻐﺎزات ﺑﺎﻟﺪم)اﻟﻀﻐﻂ اﻟﺠﺰﺋﻰ ﻟﻜﻞ ﻣﻦ اﻻآﺴﺠﻴﻦ و ﺛﺎﻧﻰ اآﺴﻴﺪ اﻟﻜﺮﺑﻮن(‪.‬‬
‫ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ﺗﻢ ﻗﻴﺎس اﻟﻤﺘﻐﻴﺮات اﻟﺴﺎﺑﻘﺔ ﻣﺮة واﺣﺪة ‪,‬ﺑﻌﺪ اﻟﻮﻻدة ﻣﺒﺎﺷﺮة ‪ .‬ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ‬
‫و اﻟﺜﺎﻟﺜﺔ ﺗﻢ ﻗﻴﺎس اﻟﻤﺘﻐﻴﺮات ﻣﺮﺗﻴﻦ ﻋﻨﺪ دﺧﻮل وﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻟﻼﻃﻔﺎل و ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ اﻟﻮﺣﺪة‬
‫ﺑﻌﺪ اﻟﻌﻼج اﻟﻼزم ﻟﻠﻤﻀﺎﻋﻔﺎت اﻟﻨﺎﺗﺠﺔ ﻋﻦ اﺻﺎﺑﺔ اﻻم ﺑﻤﺮض اﻟﺒﻮل اﻟﺴﻜﺮى‪.‬‬
‫اﻇﻬﺮت اﻟﻨﺘﺎﺋﺞ اﻻﺗﻰ‪:‬‬
‫زﻳﺎدة ﻓﻰ ﻣﻌﺪل ﺟﻠﻮآﻮز اﻟﺪم ﻓﻰ ﻧﻔﺲ اﻟﻤﺠﻤﻮﻋﺔ ﻣﻦ اﻃﻔﺎل اﻻﻣﻬﺎت اﻟﻤﺮﻳﻀﺎت ﺑﺎﻟﺴﻜﺮى ) آﻞ ﻣﻦ‬
‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ( ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ اﻟﻮﺣﺪة ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻘﻴﺎس ﻋﻨﺪ اﻟﺪﺧﻮل ‪.‬وﺟﺪ ﻧﻘﺺ ﻓﻰ ﻣﻌﺪل‬
‫ﺟﻠﻮآﻮز اﻟﺪم ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل ﻟﻮﺣﺪة اﻟﺮﻋﺎﻳﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ﻣﻊ‬
‫ﻏﻴﺎب اﻟﻔﺎرق ﻓﻰ ﻣﻌﺪل ﺟﻠﻮآﻮز اﻟﺪم ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺨﺮوج ﻣﻦ اﻟﻮﺣﺪة ﻣﻘﺎرﻧﺔ‬
‫ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ‪.‬‬
‫ﺑﺎﻟﻨﺴﺒﺔ ﻟﻤﻌﺪل اﻟﻜﺎﻟﺴﻴﻮم ﺑﺎﻟﺪم اوﺿﺤﺖ اﻟﺪراﺳﺔ وﺟﻮد زﻳﺎدة ﻓﻰ ﻣﻌﺪل اﻟﻜﺎﻟﺴﻴﻮم ﻓﻰ اﻟﺪم ﻓﻰ ﻧﻔﺲ‬
‫اﻟﻤﺠﻤﻮﻋﺔ ) آﻼ ﻣﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ( ﻗﺒﻞ اﻟﺨﺮوج ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻘﻴﺎس ﻋﻨﺪ اﻟﺪﺧﻮل ﻟﻮﺣﺪة‬
‫اﻟﺮﻋﺎﻳﺔ‪ .‬وﺟﺪ ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﻣﻌﺪل اﻟﻜﺎﻟﺴﻴﻮم ﺑﺎﻟﺪم ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ دﺧﻮل وﺣﺪة‬
‫اﻟﺮﻋﺎﻳﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ﻣﻊ اﺳﺘﻤﺮار اﻟﻨﻘﺺ ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ‬
‫اﻟﻀﺎﺑﻄﺔ ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ اﻟﻮﺣﺪة ‪.‬‬
‫آﻤﺎ ﻟﻮﺣﻆ ﻋﺪم وﺟﻮد اﺧﺘﻼف ﻣﻠﺤﻮظ ﺑﻴﻦ ﻧﺴﺒﺔ اﻟﺒﻴﻠﻴﺮوﺑﻦ اﻟﻜﻠﻰ واﻟﻤﺒﺎﺷﺮ ﻓﻰ اﻟﺪم ﻓﻰ ﻧﻔﺲ اﻟﻤﺠﻤﻮﻋﺔ ﻗﺒﻞ‬
‫اﻟﺨﺮوج و ﻋﻨﺪ دﺧﻮل اﻟﺮﻋﺎﻳﺔ ﻟﻜﻞ ﻣﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ‪.‬آﺎن هﻨﺎك زﻳﺎدة ﻣﻠﺤﻮﻇﺔ ﻓﻰ‬
‫اﻟﺒﻴﻠﻴﺮوﺑﻴﻦ اﻟﻜﻠﻰ ﻓﻰ اﻟﺪم ﺑﻴﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل وﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ وﺣﺪة اﻟﺮﻋﺎﻳﺔ‬
‫اﻟﻤﺮآﺰة ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ﻓﻰ ﺣﻴﻦ اﻧﺔ ﻻﻳﻮﺟﺪ اﺧﺘﻼف ﻣﻠﺤﻮظ ﺑﻴﻦ اﻟﺒﻴﻠﻴﺮوﺑﻴﻦ اﻟﻤﺒﺎﺷﺮ ﻓﻰ‬
‫اﻟﺪم ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ﻋﻨﺪ اﻟﺪﺧﻮل او اﻟﺨﺮوج ﻣﻦ وﺣﺪةاﻟﻌﻨﺎﻳﺔ‬
‫اﻟﻤﺮآﺰة ‪.‬‬
‫اﺛﺒﺘﺖ اﻟﺪراﺳﺔ وﺟﻮد ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﺗﺮآﻴﺰ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﺒﻦ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ ﻋﻨﺪ اﻟﺨﺮوج ﻣﻦ‬
‫وﺣﺪةاﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻘﻴﺎس ﻋﻨﺪ دﺧﻮل اﻟﻮﺣﺪة‪ .‬ﻓﻰ ﺣﻴﻦ اﻧﻪ ﻟﻢ ﻳﻼﺣﻆ اﺧﺘﻼف ﻓﻰ ﻗﻴﺎس ﻧﺴﺒﺔ‬
‫اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ ﻗﺒﻞ اﻟﺨﺮوج و ﻋﻨﺪ دﺧﻮل اﻟﺮﻋﺎﻳﺔ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻟﺜﺔ ‪ .‬وﺑﺎﻟﺮﻏﻢ ﻣﻦ ﻋﺪم وﺟﻮد اﺧﺘﻼف‬
‫ﻣﻠﺤﻮظ ﻓﻰ ﻧﺴﺒﺔ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ دﺧﻮل وﺣﺪة اﻟﺮﻋﺎﻳﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ‬
‫اﻟﻀﺎﺑﻄﺔ اﻻ اﻧﻪ ﻳﻮﺟﺪ ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﺗﺮآﻴﺰ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺨﺮوج‬
‫ﻣﻦ اﻟﻌﻨﺎﻳﺔ اﻟﻤﺮآﺰة ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ‪.‬‬
‫ﻻﻳﻮﺟﺪ اﺧﺘﻼف ﻣﻠﺤﻮظ ﺑﻴﻦ ﺣﺠﻢ اﻟﺨﻼﻳﺎ اﻟﺤﻤﺮاء اﻟﻤﻜﺪﺳﺔ ﻓﻰ اﻟﺪم ﻓﻰ ﻧﻔﺲ اﻟﻤﺠﻤﻮﻋﺔ ﻟﻜﻞ ﻣﻦ‬
‫اﻟﻤﺠﻤﻮﻋﺘﺎن اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻗﺒﻞ اﻟﺨﺮوج و ﻋﻨﺪ اﻟﺪﺧﻮل ﻟﻮﺣﺪة اﻟﺮﻋﺎﻳﺔ‪ ,‬اﻳﻀﺎ ﻟﻢ ﻳﻼﺣﻆ وﺟﻮد اﺧﺘﻼف ﻓﻰ‬
‫ﺣﺠﻢ اﻟﺨﻼﻳﺎ اﻟﺤﻤﺮاء اﻟﻤﻜﺪﺳﺔ ﻓﻰ اﻟﺪم ﺑﻴﻦ ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل ﻟﻮﺣﺪة اﻟﺮﻋﺎﻳﺔ و‬
‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ وﻟﻜﻦ آﺎن هﻨﺎك ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﺣﺠﻢ اﻟﺨﻼﻳﺎ اﻟﺤﻤﺮاء اﻟﻤﻜﺪﺳﺔ ﻓﻰ اﻟﺪم ﺑﻴﻦ‬
‫اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ وﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة واﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ‪.‬‬
‫ﺑﺎﻟﻨﺴﺒﺔ اﻟﻰ ﻣﻮأﺷﺮات اﻟﺪم ﻟﻢ ﻳﻜﻦ هﻨﺎك اﺧﺘﻼف ﻣﻠﺤﻮظ ﻓﻰ ﻣﺘﻮﺳﻂ ﺣﺠﻢ آﺮات اﻟﺪم اﻟﺤﻤﺮاء وﻣﺘﻮﺳﻂ‬
‫ﺗﺮآﻴﺰ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ وﻣﺘﻮﺳﻂ ﺗﺮآﻴﺰ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ ﻓﻰ آﻞ آﺮة ﻣﻦ آﺮات اﻟﺪم اﻟﺤﻤﺮاء وذﻟﻚ ﻓﻰ ﻧﻔﺲ‬
‫اﻟﻤﺠﻤﻮﻋﺔ ﻟﻜﻞ ﻣﻦ اﻟﻤﺠﻤﻮﻋﺘﺎن اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻗﺒﻞ اﻟﺨﺮوج و ﻋﻨﺪ د ﺧﻮل وﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة وﻟﻜﻦ‬
‫آﺎن هﻨﺎك ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﻣﺘﻮﺳﻂ ﺣﺠﻢ آﺮات اﻟﺪم اﻟﺤﻤﺮاء وﻣﺘﻮﺳﻂ ﺗﺮآﻴﺰ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ وﻣﺘﻮﺳﻂ‬
‫ﺗﺮآﻴﺰ اﻟﻬﻴﻤﻮﺟﻠﻮﺑﻴﻦ ﻓﻰ آﻞ آﺮة ﻣﻦ آﺮات اﻟﺪم اﻟﺤﻤﺮاء ﺑﺎﻟﻤﺠﻤﻮﻋﺘﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل وﻗﺒﻞ‬
‫اﻟﺨﺮوج ﻣﻦ وﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ‪.‬‬
‫ﺑﺎﻟﻨﺴﺒﺔ ﻟﻠﺨﻼﻳﺎ اﻟﺸﺒﻜﻴﺔ ﻟﻢ ﻳﻜﻦ هﻨﺎك اﺧﺘﻼف ﻣﻠﺤﻮظ ﻓﻰ ﻧﻔﺲ اﻟﻤﺠﻤﻮﻋﺔ ﻗﺒﻞ اﻟﺨﺮوج وﻋﻨﺪ دﺧﻮل ﻓﻰ آﻼ‬
‫ﻣﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ وﻟﻜﻦ آﺎن هﻨﺎك زﻳﺎدة ﻣﻠﺤﻮﻇﺔ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل‬
‫وﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ اﻟﺮﻋﺎﻳﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ‪ .‬وآﺎن هﻨﺎك راﺑﻂ اﻳﺠﺎﺑﻰ ﺑﻴﻦ ﻣﺆﺷﺮ اﻟﺨﻼﻳﺎ‬
‫اﻟﺸﺒﻜﻴﺔ واﻟﻌﻤﺮ اﻟﺤﻤﻠﻰ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ ﻋﻨﺪ دﺧﻮل اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ‪.‬‬
‫ﺑﺎﻟﻨﺴﺒﺔ ﻟﻤﻌﺎﻣﻞ ﺗﻮزﻳﻊ اﻟﻜﺮات اﻟﺤﻤﺮاء ﻋﻠﻰ اﻟﺮﻏﻢ ﻣﻦ ﻋﺪم وﺟﻮد اﺧﺘﻼف ﻣﻠﺤﻮظ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ‬
‫ﻗﺒﻞ اﻟﺨﺮوج و ﻋﻨﺪ دﺧﻮل اﻟﺮﻋﺎﻳﺔ ‪ ,‬اﻻ اﻧﻪ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻟﺜﺔ آﺎن هﻨﺎك ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﻣﻌﺎﻣﻞ‬
‫ﺗﻮزﻳﻊ اﻟﻜﺮات اﻟﺤﻤﺮاء ﻋﻨﺪ اﻟﺨﺮوج ﻣﻘﺎرﻧﺔﺑﺎﻟﻘﻴﺎس ﻋﻨﺪ دﺧﻮل اﻟﺮﻋﺎﻳﺔ ‪ .‬و آﺎن هﻨﺎك زﻳﺎدة ﻣﻠﺤﻮﻇﺔ ﻓﻰ‬
‫ﻣﻌﺎﻣﻞ ﺗﻮزﻳﻊ اﻟﻜﺮات اﻟﺤﻤﺮاء ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل ﻟﻮﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻣﻘﺎرﻧﺔ‬
‫ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ‪ .‬اﻳﻀﺎ ﻟﻢ ﻳﻼﺣﻆ وﺟﻮد اﺧﺘﻼف ﻓﻰ ﻣﻌﺎﻣﻞ ﺗﻮزﻳﻊ اﻟﻜﺮات اﻟﺤﻤﺮاء ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ‬
‫اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ اﻟﺮﻋﺎﻳﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ‪.‬‬
‫و آﺎن هﻨﺎك زﻳﺎدة ﻣﻠﺤﻮﻇﺔ ﻓﻰ ﺧﻼﻳﺎ اﻟﺪم اﻟﺒﻴﻀﺎء اﻻوﻟﻴﺔ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل‬
‫ﻟﻮﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ وﻻ ﻳﻮﺟﺪ اﺧﺘﻼف ﺑﻴﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ‬
‫ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ وﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة واﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ‪.‬‬
‫ﻋﺪد اﻟﺼﻔﺎﺋﺢ اﻟﺪﻣﻮﻳﺔ ﻟﻢ ﻳﻈﻬﺮ اى اﺧﺘﻼف ﻣﻠﺤﻮظ ﻓﻰ ﻧﻔﺲ اﻟﻤﺠﻤﻮﻋﺔ ﻗﺒﻞ اﻟﺨﺮوج و ﻋﻨﺪ اﻟﺪﺧﻮل ﻣﻦ‬
‫اﻟﺮﻋﺎﻳﺔ ﻓﻰ آﻞ ﻣﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ‪,‬ﻣﻊ وﺟﻮد ﻧﻘﺺ ﻣﻠﺤﻮظ ﻓﻰ ﻋﺪد اﻟﺼﻔﺎﺋﺢ اﻟﺪﻣﻮﻳﺔ ﻓﻰ‬
‫اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ﻋﻨﺪ اﻟﺪﺧﻮل وﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ اﻟﺮﻋﺎﻳﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ ‪.‬‬
‫أﻇﻬﺮ ﻗﻴﺎس ﺿﻐﻂ اﻟﻐﺎزات ﺑﺎﻟﺪم ﻓﻰ اﻃﻔﺎل اﻻﻣﻬﺎت اﻟﻤﺮﻳﻀﺎت ﺑﺎﻟﺴﻜﺮى وﺟﻮد ﺗﻐﻴﺮات ﻓﻰ اﻻﺗﺰان‬
‫اﻟﺤﻤﻀﻰ اﻟﻘﺎﻋﺪى ﻣﻦ ﻧﻮع اﻟﺤﻤﻮﺿﺔ اﻟﺘﻨﻔﺴﻴﺔ‪.‬‬
‫وﻧﺴﺘﻨﺘﺞ ﻣﻦ ذﻟﻚ أن ﺑﻌﺾ اﻟﺘﻐﻴﺮات اﻟﻜﻴﻤﻴﺎﺋﻴﺔ ﻓﻰ اﻃﻔﺎل اﻻﻣﻬﺎت اﻟﻤﺮﻳﻀﺎت ﺑﺎﻟﺴﻜﺮى ﻣﺜﻞ اﻧﺨﻔﺎض‬
‫ﺟﻠﻮآﻮز اﻟﺪم واﻟﻜﺎﻟﺴﻴﻮم ﻗﺪ ﺗﺤﺴﻨﺖ ﻣﻊ اﻟﻌﻼج ﺑﻮﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ﻓﻰ ﺣﻴﻦ ان ارﺗﻔﺎع اﻟﺒﻴﻠﻴﺮوﺑﻴﻦ‬
‫اﺳﺘﻤﺮ ﻓﻰ ﻧﻔﺲ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ اﻟﺜﺎﻧﻴﺔ واﻟﺜﺎﻟﺜﺔ ‪.‬ﻋﻠﻰ اﻟﺠﺎﻧﺐ اﻷﺧﺮ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ آﺎن اﻟﺘﺤﺴﻦ‬
‫ﻓﻰ اﻧﺨﻔﺎض اﻟﻜﺎﻟﺴﻴﻮم وزﻳﺎدة اﻟﺒﻴﻠﻴﺮوﺑﻦ أﺑﻄﺄ ﻣﻦ اﻟﺘﺤﺴﻦ ﻓﻰ اﻧﺨﻔﺎض ﺟﻠﻮآﻮز اﻟﺪم ‪.‬‬
‫اﻟﺰﻳﺎدة ﻓﻰ ﻣﻌﺎﻣﻞ اﻟﺨﻼﻳﺎ اﻟﺸﺒﻜﻴﺔ و اﻟﻨﻘﺺ ﻓﻰ ﻣﺆﺷﺮات اﻟﺪم اﺳﺘﻤﺮ ﺣﺘﻰ ﺧﺮوج اﻷﻃﻔﺎل ﻣﻦ وﺣﺪة‬
‫اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة‪.‬‬
‫ﻣﻌﺎﻣﻞ ﺗﻮزﻳﻊ اﻟﻜﺮات اﻟﺤﻤﺮاء اﻟﺬى ﻳﺸﻴﺮ اﻟﻰ اﺧﺘﻼف ﺣﺠﻢ اﻟﺨﻼﻳﺎ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔاﺳﺘﻤﺮ ﻓﺘﺮة اﻃﻮل‬
‫ﻣﻦ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻟﺜﺔ ‪.‬‬
‫اﻟﺰﻳﺎدة ﻓﻰ ﺧﻼﻳﺎ اﻟﺪم اﻟﺒﻴﻀﺎء اﻻوﻟﻴﺔ ﺗﺤﺴﻨﺖ ﻓﻰ ﺣﻴﻦ ان اﻟﻨﻘﺺ ﻓﻰ ﻋﺪد اﻟﺼﻔﺎﺋﺢ اﻟﺪﻣﻮﻳﺔ اﺳﺘﻤﺮ ﺣﺘﻰ‬
‫ﻗﺒﻞ اﻟﺨﺮوج ﻣﻦ وﺣﺪة اﻟﺮﻋﺎﻳﺔ اﻟﻤﺮآﺰة ‪.‬‬
‫اﻟﺘﻮﺻﻴﺎت ‪-:‬‬
‫‪-1‬اﻻآﺘﺸﺎف اﻟﻤﺒﻜﺮ ﻓﻰ اﻟﺴﺎﻋﺎت اﻻوﻟﻰ ﺑﻌﺪ اﻟﻮﻻدة اﻟﺠﺎوآﻮز ﺑﺎﻟﺪم ة ﻣﺴﺘﻮى اﻟﻜﺎﻟﺴﻴﻮم ﺣﻴﺚ ان اﻟﺘﺪﺧﻞ‬
‫ﻣﻬﻢ ﻻﻧﻘﺎذ ﺣﻴﺎة اﻃﻔﺎل اﻻﻣﻬﺎت اﻟﻤﺮﻳﻀﺎت ﺑﺎﻟﺴﻜﺮى ‪.‬‬
‫‪ -2‬اﻟﺘﻐﻴﺮات اﻟﺘﻰ ﺗﺤﺪث ﻓﻰ اﻻﺗﺰان اﻟﺤﻤﻀﻰ اﻟﻘﺎﻋﺪى هﻰ ﻣﻦ اﻟﻨﻮع اﻟﺘﻨﻔﺴﻰ ‪.‬‬
‫‪-3‬ﻣﻌﺎﻣﻞ ﺗﻮزﻳﻊ اﻟﻜﺮات اﻟﺤﻤﺮاء وارﺗﺒﺎﻃﻬﺎ ﺑﺎﻟﻴﺔ اﻟﺨﻠﻞ ﻓﻰ وﻇﻴﻔﺔ ﻋﻀﻠﺔ اﻟﻘﻠﺐ ﻳﻤﻜﻦ اﺳﺘﺨﺪاﻣﻪ ﻻﺧﺘﻴﺎر‬
‫ﻣﻦ ﺑﻴﻦ اﻃﻔﺎل اﻻﻣﻬﺎت اﻟﻤﺮﻳﻀﺎت ﺑﺎﻟﺒﻮل اﻟﺴﻜﺮى ﺑﺤﺎﺟﺔ اﻟﻰ ﻣﻮﺟﺎت ﺻﻮﺗﻴﺔ ﻋﻠﻰ اﻟﻘﻠﺐ ‪.‬‬
‫‪ -4‬ﻳﻨﺼﺢ ﺑﺎﺟﺮاء دراﺳﺎت اﺧﺮى ﻟﻠﻮﺻﻮل اﻟﻰ اﻟﻔﺘﺮات اﻟﻼزﻣﺔ ﻟﻠﻤﺘﻐﻴﺮات اﻟﺘﻰ ﻟﻢ ﺗﺘﺤﺴﻦ ﻟﺘﻌﻮد اﻟﻰ‬
‫اﻟﻘﻴﻤﺔ اﻟﻄﺒﻴﻌﻴﺔ ‪.‬‬

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My Thesis

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I would like to express my sincere appreciation and gratitude to Prof.

I am greatly thankful and grateful to Prof. Dr.Iman Abd el Salam

I would like to thank Dr. Nermeen Ahmed Al Desouky, Assistant

I would like to express my special thanks and gratitude to Prof Dr.

Shaimaa Nasr Amin

Routine investigations were performed for these neonates in the form of

Infants of diabetic mothers, gestational diabetes, pregestational diabetes,

Chapter 1: Diabetes and Pregnancy 3

Chapter 2: Infants of Diabetic Mothers 32

• Subjects and Methods 64

Akt serine/ threonine kinase

Potassium inwardly rectifying channel subfamily J,

TSB Total Serum Bilirubin

TReg T regulatory cells

Tables of the Results

19 A significant positive correlation between serum glucose 96

21 No significant correlation between gestational age and total 98

23 No significant correlation between gestational age and total 100

24 No significant correlation between staff count and 101

26 No significant correlation between staff count and 103

27 No significant correlation between reticulocytic index and 104

28 A significant positive correlation between reticulocytic index 105

31 No significant correlation between total serum bilirubin and 108

32 No significant correlation between total serum bilirubin and 109

Figures of Subjects and Methods

2 Comparison of plasma calcium level (mg/dl) among the 87

3 Comparison of serum total bilirubin (mg/dl) level among the 88

4 Comparison of serum level of direct bilirubin (mg/dl) among 88

6 Comparison of packed cell volume (%) among the studied 89

7 Comparison of total leucocytic count among the studied 90

8 Comparison of staff. Count among the studied group 90

10 Comparison of red cell distribution width among the studied 91

11 Comparison of oxygen tension (mm Hg) among the studied 92

12 Comparison of carbon dioxide tension among the studied 92

13 Comparison of bicarbonate level among the studied group 93

14 Comparison of pH among the studied group 93

15 Comparison of base deficit/excess among the studied group 94

17 A significant positive correlation between serum glucose 96

18 No significant correlation between serum glucose (mg/dl) 97

19 No significant correlation between gestational age and total 98

20 No significant correlation between gestational age and total 99

21 No significant correlation between gestational age and total 100

25 No significant correlation between reticulocytic index and 104

26 A significant positive correlation between Reticulocytic 105

29 No significant correlation between total serum bilirubin and 108

30 No significant correlation between total serum bilirubin and 109

Metabolic changes occur in normal pregnancy in response to the increase

The second change is the compensatory increase in insulin secretion by

postconception and there is an increased prevalence of congenital anomalies and

If the mother has hyperglycaemia, the fetus will be exposed to either

Infants born to mothers with glucose intolerance are at an increased risk

-Aim of the work:

The aim of this study is to investigate the effect of maternal diabetes on

Metabolism in normaal pregnaancy

Figuree (1): Oveerview of maternall /fetal nu

Glucose is the primary energy source of fetoplacental tissues. During

Glucose transfer is carried out by facilitated diffusion according to

down-regulates glucose tolerance and insulin sensitivity with decreased

-Protein and amino acid metabolism

The accretion of protein is essential for fetal growth and must be

The rate of maternal nitrogen retention between 20 and 40 weeks of

Contrary to glucose, the concentration of most amino acids in fetal