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رحيم
1
من الر
114 ة
لرحم
يةآ - طه
اهللا ال
سورة ط
بسم
س
ب
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
i
1, 25(OH)2 D 1, 25 dihydroxy vitamin D AA Autoantibodies ABG Arterial Blood Gases
ACOG American College of Obstetricians and 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
List of Abbreviations
ii
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
List of Abbreviations
iii
KCNJ11
Potassium inwardly rectifying channel subfamily J, 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
List of Abbreviations
iv
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
UGT Uridine diphosphoglucuronate Glucuronosyltransferase
UGT1A1 a specific enzyme A1 isoform of UGT VEGF Vascular endothelial growth factor VLDL Very low density lipoprotein WHO World Health Organization
List of Tables
v
Tables of Review of literature Table No.
Title Page
1 Priscilla White’s last classification for diabetes in
pregnancy modified by Pedersen
8
2 Recommended values for the diagnosis of gestational
diabetes
29
3 Normal Hemoglobin levels in neonates 56
Tables of the Results Table No.
Title Page
1 Shows mean ±standard deviation (SD) of the measured variables among studied groups
71-72
2 Paired Sample test for serum glucose and calcium at
admission and before discharge (Group II)
73
3 Paired Sample test for Arterial blood gas analysis
components at admission and before discharge (Group II)
74
4 Paired Sample test for total and direct bilirubin at admission
and before discharge (Group II)
74
5 Paired Sample test for complete Blood Count among at
admission and before discharge (Group II)
75
6 Paired Sample test for serum glucose and calcium at
admission and before discharge (Group III)
76
7
Paired Sample test for Arterial blood gas analysis
components at
admission and before discharge (Group III)
77
8 Paired Sample test for total and direct bilirubin at admission 77
List of Tables
vi
and before discharge (Group III)
9 Paired Sample test for Complete Blood Count among at
admission and before discharge (Group III)
78
10 Comparison of serum glucose and calcium in group II, group
III on admission and control group.
79
11 Comparison of Arterial Blood Gas analysis in group II,
group III on admission and control group.
80
12 Comparison of total and direct serum bilirubin in group II,
group III on admission and control group
81
13 Comparison of Complete Blood Count in control, group II
on admission and group III on admission
82
14 Comparison of serum glucose and calcium in, group II,
group III before discharge and control group.
83
15 Comparison of Arterial Blood Gas analysis in group II,
group III before discharge and control group.
84
16 Comparison of total and direct serum bilirubin in group II ,
group III before discharge and control group
84
17 Comparison of Complete Blood Count in, group II, group III
before discharge and control group
86
18 No significant correlation between serum glucose levels TSB in control group (group I)
95
19 A significant positive correlation between serum glucose level and total serum bilirubin in group II on admission
96
20 No significant correlation between serum glucose (mg/dl) levels and TSB (mg/dl) in groupIII on admission (groupIII a)
97
21 No significant correlation between gestational age and total leucocytic count in control group (group I)
98
List of Tables
vii
22 No significant correlation between gestational age and total leucocytic count group II on admission (group IIa)
99
23 No significant correlation between gestational age and total leucocytic count in groupIII on admission (group IIIa)
100
24 No significant correlation between staff count and gestational age in control group (group I)
101
25 No significant correlation between staff count and gestational age in group II on admission (group IIa)
102
26 No significant correlation between staff count and gestational age in groupIII on admission (group IIIa)
103
27 No significant correlation between reticulocytic index and gestational age in control group (group I)
104
28 A significant positive correlation between reticulocytic index and gestational age in group II on admission (group IIa)
105
29 No significant correlation between reticulocytic index and gestational age in groupIII on admission (group IIIa)
106
30 No significant correlation between total serum bilirubin and gestational age in control group (group I)
107
31 No significant correlation between total serum bilirubin and gestational age in group II on admission (group IIa)
108
32 No significant correlation between total serum bilirubin and gestational age in groupIII on admission (group IIIa)
109
List of Figures
viii
Figures of Review of literature Figure
No. Title Page
1 Overview of maternal /fetal nutrient transport and
availability
3
2 Relationship of adipose tissue lipolytic activity with
lipoprotein
7
3 Intermediary metabolism in non-pregnant ,normal
pregnancy and gestational diabetes
16
4 Summary of Potential Mechanisms of insulin resistance in
skeletal muscle during late pregnancy in human gestational
diabetes
19
5 Scheme depicting the putative sequence of events that may
take place in women with autoimmune gestational diabetes
mellitus (GDM)
23
6 Problems found in IDMs 32
7 Obesity and impaired glucose tolerance in offspring of
diabetic mothers
37
8 Hemoglobin switching 55
9 chemical structure of naturally occurring unconjugated
bilirubin
59
Figures of Subjects and Methods Figure
No. Title Page
1 New Ballard Score 66
List of Figures
ix
Figures of the Results Figure
No. Title Page
1 Comparison of plasma glucose level (mg/dl) among the
studied groups
87
2 Comparison of plasma calcium level (mg/dl) among the studied groups
87
3 Comparison of serum total bilirubin (mg/dl) level among the studied groups
88
4 Comparison of serum level of direct bilirubin (mg/dl) among the studied group
88
5 Comparison of hemoglobin level among the studied group
89
6 Comparison of packed cell volume (%) among the studied group
89
7 Comparison of total leucocytic count among the studied group
90
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 group
91
11 Comparison of oxygen tension (mm Hg) among the studied group
92
12 Comparison of carbon dioxide tension among the studied group
92
13 Comparison of bicarbonate level among the studied group
93
14 Comparison of pH among the studied group
93
List of Figures
x
15 Comparison of base deficit/excess among the studied group 94 16 No significant correlation between serum glucose level TSB
in control group (group I)
95
17 A significant positive correlation between serum glucose level and total serum bilirubin in group II on admission
96
18 No significant correlation between serum glucose (mg/dl) levels and TSB (mg/dl) in groupIII on admission (group IIIa)
97
19 No significant correlation between gestational age and total leucocytic count in control group (Group I)
98
20 No significant correlation between gestational age and total leucocytic count in group II on admission (group IIa)
99
21 No significant correlation between gestational age and total leucocytic count in groupIII on admission (group IIIa)
100
22 No significant correlation between staff count and gestational age in control group (group I)
101
23 No significant correlation between staff count and gestational age in group II on admission (group IIa)
102
24 No significant correlation between staff count and gestational age in groupIII on admission (group IIIa)
103
25 No significant correlation between reticulocytic index and gestational age in control group (group I)
104
26 A significant positive correlation between Reticulocytic index and gestational age in group II on admission (group IIa)
105
27 No significant correlation between reticulocytic index and gestational age in groupIII on admission (group IIIa)
106
List of Figures
xi
28 No significant correlation between total serum bilirubin and gestational age in control group (group I)
107
29 No significant correlation between total serum bilirubin and gestational age in group II on admission (group IIa)
108
30 No significant correlation between total serum bilirubin and gestational age in groupIII on admission (group IIIa)
109
Introduction and aim of the work
1
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
Introduction and aim of the work
2
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.
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Chapter I Review of Literature
4
-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
Chapter I Review of Literature
5
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).
Chapter I Review of Literature
6
-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).
Chapter I Review of Literature
7
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).
Chapter I Review of Literature
8
-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.
Chapter I Review of Literature
9
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).
Chapter I Review of Literature
10
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).
Chapter I Review of Literature
11
-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).
Chapter I Review of Literature
12
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).
Chapter I Review of Literature
13
-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).
Chapter I Review of Literature
14
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).
Chapter I Review of Literature
15
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).
Chapter
I
16
Review of LLiterature
Chapter I Review of Literature
17
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
Chapter I Review of Literature
18
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).
Chapter
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Chapter I Review of Literature
20
(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).
Chapter I Review of Literature
21
-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
Chapter I Review of Literature
22
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
Chapter
autoim
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Chapter I Review of Literature
24
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).
Chapter I Review of Literature
25
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
Chapter I Review of Literature
26
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).
Chapter I Review of Literature
27
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).
Chapter I Review of Literature
28
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).
Chapter I Review of Literature
29
Recommendation for diagnosis of GDM Plasma glucose level (mg/dl)
ACOG National Diabetes Data Group (USA)
-Fasting glucose
-One-hour post-100-g load
-Two-hour post-100-g load
-Three-hour post-100-g load
105
190
165
145
American Diabetes Association (USA)
-Fasting glucose
-One-hour post-100-g load
-Two-hour post-100-g load
-Three-hour post-100-g load
95
180
155
140 WHO 1998
-Fasting glucose
-Two-hour post-75-g load
126
180 ADIPS
-Fasting glucose
-Two-hour post-75-g load
99
144
NZSSD
-Fasting glucose
-Two-hour post-75-g load
99
162
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).
Chapter I Review of Literature
30
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).
Chapter I Review of Literature
31
-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).
Chapter
mortal
develo
infants
and m
glucos
diabete
diabete
Figure
Newbo
II
Diabetes
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Vein Thro
32
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Chapter II Review of Literature
33
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).
Chapter II Review of Literature
34
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).
Chapter II Review of Literature
35
-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
Chapter II Review of Literature
36
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
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Chapter II Review of Literature
38
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
Chapter II Review of Literature
39
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
Chapter II Review of Literature
40
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).
Chapter II Review of Literature
41
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).
Chapter II Review of Literature
42
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
Chapter II Review of Literature
43
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,
Chapter II Review of Literature
44
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).
Chapter II Review of Literature
45
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.
Chapter II Review of Literature
46
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).
Chapter II Review of Literature
47
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
Chapter II Review of Literature
48
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
Chapter II Review of Literature
49
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,
Chapter II Review of Literature
50
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).
Chapter II Review of Literature
51
-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).
Chapter II Review of Literature
52
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).
Chapter II Review of Literature
53
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
Chapter II Review of Literature
54
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.
Chapter
Figure
Norm
proper
been d
infants
age is
noticed
premat
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II
e (8): Hem
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A clear d
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oglobin Le
definition
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wk in ter
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ause shoul
switching
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anagemen
h measure
mal range
a. A “phy
rm infants
g/dL). If
ld be initia
55
g (Stockm
normal ha
nt. Normal
ement of
e of hemog
siologic”
(hemoglo
f anemia i
ated (Bizz
man and P
aemoglobi
l haemogl
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Pochedly 1
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1988).
is importa
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Literature
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ostnatal
ntent is
6 wk in
careful
Chapter II Review of Literature
56
AGE
Gestational
(weeks)
HEMOGLOBIN
(g/dL)
HEMATO
CRIT (%) MCV (μ3)
RETICULOCYTES
(%)
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).
Chapter II Review of Literature
57
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).
Chapter II Review of Literature
58
-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).
Chapter
-Form
major
haemo
oxidati
enzym
methan
(CO)
subseq
2008;
Figure
bilirub
II
mation, Str
Bilirubin
source i
oglobin inv
ive proce
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ne bridge
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rubin M
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structure
.
59
etabolism
erties of B
ct of the c
moglobin.
the iron an
he enzyme
othelial sy
phyrin ring
One mole
for each m
e of nat
m and ID
Bilirubin
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Review of L
me, of whi
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Literature
ich the
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Fevery,
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Chapter II Review of Literature
60
-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
Chapter II Review of Literature
61
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).
Chapter II Review of Literature
62
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
Chapter II Review of Literature
63
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).
Subjects and Methods
64
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).
Subjects and Methods
65
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.
-Meth
neurom
files. T
criteria
tone is
betwee
2006).
Neurol
2009).
hodology
The gest
muscular m
The exam
a. The neu
s more use
en two ob
It slightl
logical si
Fig (
y:
tational a
maturity a
mination co
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eful than a
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ly overest
gns are m
(1): NewB
age asses
and physic
onsists of
lar criteria
active tone
n NBS as
timates th
more relia
Ballard Sc
66
ssed by
cal maturi
f six neuro
a are base
e in indica
ssessment
he GA wit
able than
core (Mar
New Ba
ity and it
omuscular
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understand
ational age
ne (Marín
sing postn
ones (Sas
iel et al., 2
Subjects and
ore (NBS
ided in ne
and six ph
ding that p
e. The agre
n Gabriel
natal age (
sidharan
2006)
d Methods
S), for
eonates
hysical
passive
eement
et al.,
(PNA).
et al.,
Subjects and Methods
67
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.
Subjects and Methods
68
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= 1
2
−nd
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
Subjects and Methods
69
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).
Subjects and Methods
70
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.
Results
71
Results
A-Descriptive statistics
Table (1): Shows mean ±standard deviation (SD) of the measured variables among studied groups
Parameter
Control(n=20)Group IIa (n=20)
Group IIb (n=20)
Group IIIa (n=20)
Group IIIb (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
Results
72
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.
Results
73
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
-As revealed from table (3):
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).
Results
74
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). Pairs t Sig. (2-tailed)
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) Pairs t Sig. (2-tailed)
TSB2 - TSB1 -1.243 .229
DSB2 - DSB1 -1.002 .329
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
Results
75
-As revealed from table (5):
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). Pairs t Sig. (2-tailed)
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.
Results
76
-Group III (IDMs whose mothers had gestational diabetes)
-As revealed from table (6):
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).
Pairs t Sig. (2-tailed)
Glucose2 - Glucose1 2.275 .035*
Calcium2 - Calcium1 7.850 .000*
*P<0.05=Significant
-As revealed from table (7):
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).
Results
77
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). Pairs t Sig. (2-tailed)
TSB2 - TSB1 .877 .392
DSB2 - DSB1 .895 .382
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin.
-As revealed from table (9):
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
Results
78
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). Pairs t Sig. (2-tailed)
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.
Results
79
2-Analysis of Variance (ANOVA) test
-Comparison between variables on admission in group II and group III and
control group:
-As revealed from table (10):
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
(n=20)
Group IIa
(n=20)
Group IIIa
(n=20)
P-value
Glucose (mg/dl) 84.25±14.414 49.95±20.493 65.45±41.140 0.000*
Calcium (mg/d)l 9.80±.894 7.68±1.348 7.34±1.203 0.000*
*P<0.05= significant
-As revealed from table (11):
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
Results
80
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
Parameter
Control
(n=20)
Group IIa
(n=20)
Group IIIa
(n=20)
P-value
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*
*P<0.05= significant
-As revealed from table (12):
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).
Results
81
Table (12) Comparison of total and direct serum bilirubin in group II,
group III on admission and control group.
Measured
Parameter
Control
(n=20)
Group IIa
(n=20)
Group IIIa
(n=20)
P-value
TSB(mg/dl) 2.79±1.261 9.80±5.807 5.81±3.898 0.000*
DSB(mg/dl) 0.80±.433 1.42±2.857 0.56±.239 0.180
*P<0.05= significant
TSB=Total Serum Bilirubin, DSB =Direct Serum Bilirubin
-As revealed from table (13):
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%).
Results
82
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. Measured
Parameter
Control
(n=20)
Group IIa
(n=20)
Group IIIa
(n=20)
P-value
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
9
244.90±113.973 181.55±106.119 0.000*
*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.
Results
83
-Comparison between variables before discharge in group II and group III
and control group:
-As revealed from table (14):
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
Parameter
Control
(n=20)
Group IIb
(n=20)
Group IIIb
(n=20)
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*
*P<0.05= significant
-As revealed from table (15):
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.
Results
84
Table (15) Comparison of Arterial Blood Gas analysis in group II, group
III before discharge and control group.
Measured
Parameter
Control
(n=20)
Group IIb
(n=20)
Group IIIb
(n=20)
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
-As revealed from table (16):
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,
group III before discharge and control group.
Measured
Parameter
Control
(n=20)
Group IIb
(n=20)
Group IIIb
(n=20)
P-value
TSB(mg/dl) 2.79±1.261 7.89±4.197 6.82±4.068 0.000*
DSB(mg/dl) 0.80±.433 0.74±.446 0.64±.343 0.451
*P<0.05= significant
Results
85
-As revealed from table (17):
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).
Results
86
Table (17) Comparison of Complete Blood Count in, group II, group III
before discharge and control group.
Measured
Parameter
Control
(n=20)
Group IIb
(n=20)
Group IIIb
(n=20)
P-value
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,
Results
Figure
group
*signifi
Figuregroup
1
1
0
2
4
6
8
10
12
mg/
e (1) Com
s
icant P as co
e (2): Coms
0
20
40
60
80
100
120
mg/dl
/dl
*
mparison o
ompared to
mparison
84.25
control
9.8
control
significant P
of serum
control
of serum
49.95
G
groupIIa
7.675
Grou
groupIIa
87
P as compa
glucose le
m calcium
84.25
Group
GlucoseGroupA
groupIIb
8.59
Group
CalciupA*and
groupIIb
ared to contr
evel (mg/d
level (mg
65.45
eA*
groupIIIa
7.335
iumd Group
groupIIIa
rol
dl) among
g/dl) amon
88.15
groupIIIb
8.71
p B*
groupIIIb
g the stud
ng the stu
b
died
udied
Results
*signifi
Figurestudie
Figurethe stu
1
1
2
‐2
‐1
0
1
2
3
4
5
mg/d
icant P as co
e (3): Comed groups
e (4): Comudied gro
0
5
10
15
20
0.
mg/dl
dl
ompared to
mparison
mparison up
2.79
control
8051.4
control gr
control
of serum
of serum
9.795
Grou
groupIIa
4170.74
Gro
DS
roupIIa gr
88
m total bili
m level of d
7.89
Group
TSBpA* and
groupIIb
425 0.5
oup
SB
roupIIb gro
irubin (m
direct bili
5.81
Bd Group
groupIIIa
56 0.64
oupIIIa gr
g/dl) leve
irubin (m
6.818
pB*
groupIII
4
roupIIIb
el among t
g/dl) amo
b
the
ong
Results
*signifi
Figure
*signif
Figuregroup
1
1
2
2
1
2
3
4
5
6
7
gl
icant P as co
e (5): Com
ficant P as
e (6): Com
0
5
10
15
20
25
0
10
20
30
40
50
60
70
%
gm/dl
ompared to
mparison
compared
mparison
16.95263158
control
53.09
control
control
of hemog
d to contro
of packed
17.115
G
groupIIa
52.45
groupIIa
89
globin lev
ol
d cell volu
16.3114
Group
HbGroupB*
groupIIb
50.83
PCVGroup
groupIIb
vel among
ume (%)
4.48947368
*
groupIIIa
45.54
B*
groupIIIa
g the studi
among th
14.075
groupIIIb
43.72
groupIIIb
ied group
he studied
p
d
Results
Figure
*signif
Figure
‐
1
1
2
10
e (7): Com
ficant P as
e (8): Com
0
5
10
15
20
25
30
‐5
0
5
10
15
20
000/cmm
%
mparison
compared
mparison
17.85
control
3.3
control
of total le
d to contro
of staff. C
15.36
groupIIa
7.35
groupIIa
90
eucocytic
ol
Count am
15.73
Group
TLC
groupIIb
6.1
Group
StaffGroupA
groupIIb
count am
mong the s
16.8751
groupIIIa
9.65
A*
groupIIIa
mong the s
studied gr
15.335
a group
5.55
groupIIIb
studied gr
roup
IIIb
b
roup
Results
*signif
Figure
*signif
Figuregroup
1
2
3
4
5
1
1
2
2
3
10
ficant P as
e (9): Com
ficant P as
e (10): Co
0
100
200
300
400
500
0
5
10
15
20
25
30
000/cmm
%
compared
mparison
compared
omparison
332.75
control
16.085
control
d to contro
of platele
d to contro
n of red c
244.9
Group
groupIIa
18.94
groupIIa
91
ol
ets counts
ol
cell distrib
237.85
Group
PlatelepA* and
groupIIb
18.39
Group
RDWGroupA
groupIIb
s among t
bution wid
181.55
etsd Group
groupIIIa
20.125
WA*
groupIIIa
the studie
dth amon
222.25
B*
groupIIIb
18.95
groupIIIb
d group
ng the stud
b
died
Results
*signif
Figuregroup
*signif
Figuregroup
0
20
40
60
80
m
m
ficant P as
e (11): Co
ficant P as
e (12): Co
0
20
40
60
80
100
120
mmHg
mHg
compared
omparison
compared
omparison
40.145
control
88.06
control
d to contro
n of oxyge
d to contro
n of carbo
52.685
G
groupIIa
47.715
groupIIa
92
ol
en tension
ol
on dioxid
38.495
Pco2GroupA
groupIIb
89.275
Group
PO2Group
groupIIb
n (mm Hg
e tension
42.97
*
groupIIIa
63.79
2A*
groupIIIa
g) among
among th
36.285
groupIIIb
90.315
groupIIIb
the studi
he studied
ied
d
Results
*signif
Figure
*signif
Figure
1
1
2
2
3
6.8
6.9
7
7.1
7.2
7.3
7.4
7.5
7.6
ficant P as
e (13): Co
ficant P as
e (14): Co
0
5
10
15
20
25
30
c
mEq/L
compared
omparison
compared
omparison
21.345
control
7.391
7
ontrol gr
d to contro
n of bicar
d to contro
n of pH a
22
G
groupIIa
7.23635
Gr
roupIIa g
93
ol
rbonate le
ol
mong the
22.71
Group
HCO3GroupB
groupIIb
7.38457.3
Group
pHroupA*
roupIIb g
evel amon
e studied g
19.15
*
groupIIIa
06315789
groupIIIa
ng the stud
group
22.91
groupIIIb
7.4065
groupIIIb
died grou
ups
Results
*signif
Figure
‐8
‐6
‐4
‐2
0
2
4
ficant P as
e (15): Co
compared
omparison
‐1.16
control
d to contro
n of base
‐3.82
groupIIa
94
ol
deficit/ex
‐1.68
BE/BD 1
BE/Grou
groupIIb
xcess amo
‐5.965
/BDup A*
groupIIIa
ng the stu
‐2.085
groupIIIb
udied gro
b
up
Results
95
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
Sig. (2-tailed) .068
Figure (16): No significant correlation between serum glucose level TSB in control group (group I)
Results
96
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*
Sig. (2-tailed) .040
TSB1 Pearson Correlation .463* 1
Sig. (2-tailed) .040
Figure (17): A significant positive correlation between serum glucose level and total serum bilirubin in group II on admission
Results
97
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
Sig. (2-tailed) .615
TSB1 Pearson Correlation -.120 1
Sig. (2-tailed) .615
Figure (18): No significant correlation between serum glucose (mg/dl) levels and TSB (mg/dl) in groupIII on admission (group IIIa)
Results
98
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
Sig. (2-tailed) .924
TLC Pearson Correlation .023 1
Sig. (2-tailed) .924
Figure (19): No significant correlation between gestational age and total leucocytic count in control group (Group I)
Results
99
B- Correlation between gestational age and total leucocytic count group II on admission (group IIa) Table (22): No significant correlation between gestational age and total leucocytic count group II on admission (group IIa)
GA(WKs) TLC1
GA(WKs) Pearson Correlation 1 .008
Sig. (2-tailed) .973
TLC1 Pearson Correlation .008 1
Sig. (2-tailed) .973
Figure (20): No significant correlation between gestational age and total leucocytic count in group II on admission (group IIa)
Results
100
C-Correlation between gestational age and total leucocytic count in groupIII on admission (group IIIa) Table (23): No significant correlation between gestational age and total leucocytic count in groupIII on admission (group IIIa)
GA(WKs) TLC1
GA(WKs) Pearson Correlation 1 .022
Sig. (2-tailed) .927
TLC1 Pearson Correlation .022 1
Sig. (2-tailed) .927
Figure (21): No significant correlation between gestational age and total leucocytic count in groupIII on admission (group IIIa)
Results
101
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
GA(WKs) Pearson Correlation 1 .145
Sig. (2-tailed) .541
staff. Pearson Correlation .145 1
Sig. (2-tailed) .541
Figure (22): No significant correlation between staff count and gestational age in control group (group I)
Results
102
B-Correlations between staff count and gestational age in group II on admission (group IIa) Table (25): No significant correlation between staff count and gestational age in group II on admission (group IIa)
GA(WKs) staff.1
GA(WKs) Pearson Correlation 1 .033
Sig. (2-tailed) .891
staff.1 Pearson Correlation .033 1
Sig. (2-tailed) .891
Figure (23): No significant correlation between staff count and gestational age in group II on admission (group IIa)
Results
103
C-Correlations between staff count and gestational age in groupIII on admission (group IIIa) Table (26): No significant correlation between staff count and gestational age in groupIII on admission (group IIIa)
GA(WKs) staff.1
GA(WKs) Pearson Correlation 1 .032
Sig. (2-tailed) .894
N 20 20
staff.1 Pearson Correlation .032 1
Sig. (2-tailed) .894
N 20 20
Figure (24): No significant correlation between staff count and gestational age in groupIII on admission (group IIIa)
Results
104
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 gestational age in control group (group I)
GA(WKs)
RETICULOCYT
E INDEX
GA(WKs) Pearson Correlation 1 .227
Sig. (2-tailed) .337
RETICULOCYTE INDEX Pearson Correlation .227 1
Sig. (2-tailed) .337
Figure (25): No significant correlation between reticulocytic index and gestational age in control group (group I)
Results
105
B-Correlation between Reticulocytic index and gestational age in group II on admission (group IIa) Table (28): A significant positive correlation between reticulocytic index and gestational age in group II on admission (group IIa)
GA(WKs)
RETICULOCYT
E INDEX
GA(WKs) Pearson Correlation 1 .504*
Sig. (2-tailed) .023
RETICULOCYTE INDEX Pearson Correlation .504* 1
Sig. (2-tailed) .023
*. Correlation is significant at the 0.05 level (2-tailed).
Figure (26): A significant positive correlation between Reticulocytic index and gestational age in group II on admission (group IIa)
Results
106
C- Correlation between reticulocytic index and gestational age in groupIII on admission (group IIIa) Table (29): No significant correlation between reticulocytic index and gestational age in groupIII on admission (group IIIa)
GA(WKs)
RETICULOCYT
E INDEX
GA(WKs) Pearson Correlation 1 .105
Sig. (2-tailed) .659
RETICULOCYTE INDEX Pearson Correlation .105 1
Sig. (2-tailed) .659
Figure (27): No significant correlation between reticulocytic index and gestational age in groupIII on admission (group IIIa)
Results
107
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 gestational age in control group (group I)
GA(WKs) TSB
GA(WKs) Pearson Correlation 1 .058
Sig. (2-tailed) .810
TSB Pearson Correlation .058 1
Sig. (2-tailed) .810
Figure (28): No significant correlation between total serum bilirubin and gestational age in control group (group I)
Results
108
B- Correlations between total serum bilirubin and gestational age in group II on admission (group IIa) Table (31): No significant correlation between total serum bilirubin and gestational age in group II on admission (group IIa)
GA(WKs) TSB1
GA(WKs) Pearson Correlation 1 -.026
Sig. (2-tailed) .915
TSB1 Pearson Correlation -.026 1
Sig. (2-tailed) .915
Figure (29): No significant correlation between total serum bilirubin and gestational age in group II on admission (group IIa)
Results
109
C- Correlations between total serum bilirubin and gestational age in groupIII on admission (group IIIa) Table (32): No significant correlation between total serum bilirubin and gestational age in groupIII on admission (group IIIa)
GA(WKs) TSB1
GA(WKs) Pearson Correlation 1 -.134
Sig. (2-tailed) .573
TSB1 Pearson Correlation -.134 1
Sig. (2-tailed) .573
Figure (30): No significant correlation between total serum bilirubin and gestational age in groupIII on admission (group IIIa)
Discussion
110
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.
Discussion
111
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
Discussion
112
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).
Discussion
113
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
Discussion
114
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).
Discussion
115
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).
Discussion
116
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).
Discussion
117
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.
Discussion
118
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.
Discussion
119
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.
Discussion
120
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
Discussion
121
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).
Discussion
122
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
Discussion
123
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.
Discussion
124
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
Discussion
125
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).
Summary and Conclusion
126
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.
Summary and Conclusion
127
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
Summary and Conclusion
128
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
Summary and Conclusion
129
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.
Summary and Conclusion
130
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.
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الملخص العربى
اطفال . ان االصابة بمرض السكرى اثناء الحمل يزيد معدالت االعتالل والوفيات لكل من االم و الطفل
دة ازي,نمو غير طبيعى,هات المريضات بالسكرى يكونون اآثر عرضه لالصابة بصعوبة فى التنفسماال
النمو العصبي على نتائج سلبية ,بالدم نقص فى ترآيز السكر ,لبيليروبينزيادة فى نسبة ا,ى لزوجة الدمف
.و تشوهات القلب واألوعية الدموية,نقص فى ترآيز الكالسيوم و الما غنسيوم بالدم,عيوب خلقية,
التى تحدث فى في هذا البحث تم دراسة تاثير اصابة االم بمرض السكرى على حدوث بعض التغيرات
و تأثير العالج بوحدة نلدى ابنائه المذابة فى البالزماالكيميائية عناصر الدم و آذلك ترآيز العناصر
.ثى الوالدة على هذه التغيراتالرعاية المرآزة لالطفال حدي
تم ,اسبوع 41الى 32العمر الحملي لهم يتراوح من , تم اجراء البحث على ستين طفل حديث الوالدة
:تقسيمهم الى ثالثة مجموعات
من اى نوال تعانى امهاته و تتكون من عشرين طفل طبيعي):طةبالمجموعة الضا(:المجموعة االولى
.قبل او اثناء الحمل امراض
آال (بمرض السكرى قبل حدوث الحمل اتمصاب نتهتتكون من عشرين طفل امها: المجموعة الثانية
.)االول و الثانى,النوعين
.الحمل اثناءبمرض السكرى ن اصبنتتكون من عشرين طفل امهاته :المجموعة الثالثة
بالدم مع عمل و البيكربوناتبيليروبينلسيوم و الوالكافى الثالث مجموعات تم قياس مستوى الجلوآوز
. )الضغط الجزئى لكل من االآسجين و ثانى اآسيد الكربون(صورة دم آاملة و قياس الغازات بالدم
فى المجموعة الثانية . الدة مباشرة بعد الو,فى المجموعة الضابطة تم قياس المتغيرات السابقة مرة واحدة
و الثالثة تم قياس المتغيرات مرتين عند دخول وحدة الرعاية المرآزة لالطفال و قبل الخروج من الوحدة
.بعد العالج الالزم للمضاعفات الناتجة عن اصابة االم بمرض البول السكرى
:اظهرت النتائج االتى
آل من ( فى نفس المجموعة من اطفال االمهات المريضات بالسكرى الدم جلوآوز معدل زيادة فى
فى معدل وجد نقص .قبل الخروج من الوحدة مقارنة بالقياس عند الدخول ) المجموعة الثانية والثالثة
مع المجموعة الضابطةمقارنة ب عند الدخول لوحدة الرعاية الثانية والثالثة المجموعتين الدم فى جلوآوز
مقارنةن الثانية والثالثة عند الخروج من الوحدة يبالمجموعت الدم جلوآوز ارق فى معدلغياب الف
. بالمجموعة الضابطة
معدل الكالسيوم بالدم اوضحت الدراسة وجود زيادة فى معدل الكالسيوم فى الدم فى نفس لبالنسبة
لوحدة بالقياس عند الدخولمقارنة قبل الخروج ) الثانية والثالثة تينمن المجموع آال( المجموعة
ن الثانية والثالثة عند دخول وحدة يبالمجموعت ملكالسيوم بالدمعدل ا فىنقص ملحوظ وجد . الرعاية
المجموعة ب مقارنة ن الثانية والثالثةيبالمجموعتنقص المجموعة الضابطة مع استمرار الب مقارنة الرعاية
.الضابطة قبل الخروج من الوحدة
قبل ملحوظ بين نسبة البيليروبن الكلى والمباشر فى الدم فى نفس المجموعة وجود اختالفآما لوحظ عدم
فى زيادة ملحوظةآان هناك .ن الثانية والثالثة لمجموعتيالرعاية لكل من االخروج و عند دخول
الرعاية ن الثانية والثالثة عند الدخول وقبل الخروج من وحدةيالمجموعت البيليروبين الكلى فى الدم بين
اختالف ملحوظ بين البيليروبين المباشر فى فى حين انة اليوجدالضابطة المجموعةب مقارنة المرآزة
عند الدخول او الخروج من وحدةالعناية المجموعة الضابطة ب مقارنة ن الثانية والثالثةيبالمجموعتالدم
.المرآزة
عند الخروج من الهيموجلوببن فى المجموعة الثانيةفى ترآيز نقص ملحوظ اثبتت الدراسة وجود
فى حين انه لم يالحظ اختالف فى قياس نسبة .الوحدة عند دخول مقارنة بالقياس الرعاية المرآزةوحدة
وبالرغم من عدم وجود اختالف . دخول الرعاية فى المجموعة الثالثة عند قبل الخروج و الهيموجلوبين
المجموعة ب مقارنة عند دخول وحدة الرعاية بالمجموعتن الثانية والثالثة الهيموجلوبينملحوظ فى نسبة
عند الخروج المجموعتن الثانية والثالثة فى الهيموجلوبينفى ترآيز نقص ملحوظ اال انه يوجد الضابطة
.المجموعة الضابطة ب مقارنة من العناية المرآزة
لكل من ا الحمراء المكدسة فى الدم فى نفس المجموعة اليوجد اختالف ملحوظ بين حجم الخالي
ايضا لم يالحظ وجود اختالف فى ,وحدة الرعايةلخول دعند ال و قبل الخروج لثالثةاالمجموعتان الثانية و
و عند الدخول لوحدة الرعاية ن الثانية والثالثةيبالمجموعت حجم الخاليا الحمراء المكدسة فى الدم بين
حجم الخاليا الحمراء المكدسة فى الدم بين فىنقص ملحوظ المجموعة الضابطة ولكن آان هناك
. موعة الضابطة المجون الثانية والثالثة قبل الخروج من وحدة الرعاية المرآزة يالمجموعت
ومتوسط سط حجم آرات الدم الحمراء شرات الدم لم يكن هناك اختالف ملحوظ فى متووأبالنسبة الى م
الهيموجلوبين فى آل آرة من آرات الدم الحمراء وذلك فى نفس ترآيز ومتوسط الهيموجلوبين ترآيز
خول وحدة الرعاية المرآزة ولكن د عند و قبل الخروج المجموعة لكل من المجموعتان الثانية والثالثة
ومتوسط الهيموجلوبين ترآيز فى متوسط حجم آرات الدم الحمراء ومتوسطنقص ملحوظ آان هناك
عند الدخول وقبل بالمجموعتن الثانية والثالثة الهيموجلوبين فى آل آرة من آرات الدم الحمراء ترآيز
.المجموعة الضابطةب مقارنة الخروج من وحدة الرعاية المرآزة
آال ىف خولدوعند قبل الخروج اختالف ملحوظ فى نفس المجموعة هناك بالنسبة للخاليا الشبكية لم يكن
خول دعند ال ن الثانية والثالثةيالمجموعت فى زيادة ملحوظة كن الثانية والثالثة ولكن آان هنايمن المجموعت
بط ايجابى بين مؤشر الخاليا اوآان هناك ر. المجموعة الضابطةب مقارنة وقبل الخروج من الرعاية
.المرآزة الشبكية والعمر الحملى فى المجموعة الثانية عند دخول الرعاية
وجود اختالف ملحوظ فى المجموعة الثانيةعدم بالنسبة لمعامل توزيع الكرات الحمراء على الرغم من
فى معاملنقص ملحوظ آان هناك مجموعة الثالثةال فىاال انه ,خول الرعاية دعند و قبل الخروج
فى زيادة ملحوظة و آان هناك .خول الرعاية د بالقياس عندمقارنة الخروج توزيع الكرات الحمراء عند
مقارنة وحدة الرعاية المرآزةل عند الدخول ن الثانية والثالثةيالمجموعت فىمعامل توزيع الكرات الحمراء
ن يالمجموعت معامل توزيع الكرات الحمراء فىايضا لم يالحظ وجود اختالف فى . المجموعة الضابطةب
.المجموعة الضابطةبمقارنة قبل الخروج من الرعاية الثانية والثالثة
عند الدخول ن الثانية والثالثةيالمجموعت فى خاليا الدم البيضاء االولية فى زيادة ملحوظة و آان هناك
ن الثانية والثالثةيالمجموعت وال يوجد اختالف بين المجموعة الضابطةبلوحدة الرعاية المرآزة مقارنة
.المجموعة الضابطة وقبل الخروج من وحدة الرعاية المرآزة
من عند الدخول و قبل الخروج نفس المجموعة فى عدد الصفائح الدموية لم يظهر اى اختالف ملحوظ
فى فى عدد الصفائح الدموية نقص ملحوظمع وجود , ن الثانية والثالثةيالرعاية فى آل من المجموعت
. المجموعة الضابطةبمقارنة الرعايةخول وقبل الخروج من دعند ال ن الثانية والثالثةيالمجموعت
الغازات بالدم فى اطفال االمهات المريضات بالسكرى وجود تغيرات فى االتزان ضغط أظهر قياس
.الحمضى القاعدى من نوع الحموضة التنفسية
خفاض نمثل ا بالسكرىونستنتج من ذلك أن بعض التغيرات الكيميائية فى اطفال االمهات المريضات
ليروبين يتحسنت مع العالج بوحدة الرعاية المرآزة فى حين ان ارتفاع الب قدالكالسيوم والدم جلوآوز
المجموعة الضابطة آان التحسن بمقارنة على الجانب األخر . ن الثانية والثالثةيالمجموعت استمر فى نفس
. الدم انخفاض جلوآوز ليروبن أبطأ من التحسن فى يالكالسيوم وزيادة الب انخفاضفى
حتى خروج األطفال من وحدة الزيادة فى معامل الخاليا الشبكية و النقص فى مؤشرات الدم استمر
.الرعاية المرآزة
معامل توزيع الكرات الحمراء الذى يشير الى اختالف حجم الخاليا فى المجموعة الثانيةاستمر فترة اطول
. من المجموعة الثالثة
ح الدموية استمر حتى ئاالولية تحسنت فى حين ان النقص فى عدد الصفاالزيادة فى خاليا الدم البيضاء
.قبل الخروج من وحدة الرعاية المرآزة
-:التوصيات
توى الكالسيوم حيث ان التدخل االآتشاف المبكر فى الساعات االولى بعد الوالدة الجاوآوز بالدم ة مس- 1
. اطفال االمهات المريضات بالسكرىمهم النقاذ حياة
.التغيرات التى تحدث فى االتزان الحمضى القاعدى هى من النوع التنفسى - 2
معامل توزيع الكرات الحمراء وارتباطها بالية الخلل فى وظيفة عضلة القلب يمكن استخدامه الختيار - 3
.من بين اطفال االمهات المريضات بالبول السكرى بحاجة الى موجات صوتية على القلب
الزمة للمتغيرات التى لم تتحسن لتعود الى لدراسات اخرى للوصول الى الفترات ا ينصح باجراء - 4
.القيمة الطبيعية