Donald School Textbook of Diabetic Pregnancy and Ultrasound Asim Kurjak, Badreldeen Ahmed
INDEX
Page numbers followed by b refer to box, f refer to figure, and t refer to table.
A
Addison's disease 123
Adenosine triphosphate-sensitive potassium 111
ADHDs See Attention deficit hyperactivity disorders
Adipokines 141
Adiponectin 141
Adipose tissue, endocrine function of 141
Adrenomedullary system 140
Adverse pregnancy outcome 136
Amylin 24
Amyloid polypeptide 24
Anal atresia 93
perineum in 102f
Anal mucosa 102f
Anal sphincter muscles 102f
Anechoic cystic areas in kidney, multiple 84f
Antenatal corticosteroid
implications of 124
therapy 127, 128
Antenatal prophylactic administration, indications for 124
Antenatal steroid therapy, require 129
Aorta 69, 96
Aortic arch in sagittal section 68f
Asphyxia 112
B
Banana sign 98
Bariatric surgery 144
Beckwith-Wiedemann syndrome 110, 114
Beta-cell dysfunction 105
Betamethasone 123, 124, 127
Birth trauma 4
Blood glucose
levels 127
preprandial 8
BMI See Body mass index
Body mass index 2, 134, 135, 136, 140
C
Canadian Diabetes Association 27
Carbohydrate metabolic changes of pregnancy 141
Cardiac anomalies 65, 95
Cardiovascular system 36
Catch-down growth pattern 112, 113
Caudal dysplasia 93
Caudal regression syndrome 65, 93, 94, 94f, 95, 95f, 113
characteristic elements of 93t
diagnosis of 94
CDA See Canadian Diabetes Association
Central nervous system 35, 46, 64, 74
anomalies 98
Chiari II malformation 98
Chronic disease, development of degenerative and 144
Congenital anomalies
impact of 92
incidence of 92
risk of major 92
Congenital cardiac anomalies 64
Congenital heart disease 36, 65, 80
Congenital malformation, diagnosis of 34, 130
Conotruncal anomalies 66
diagnosis of 66
Cortisol 2
Cranial end defects 74
Cranial regressions syndrome 35
Cranium in transthallamic section 79f
Cyanotic congenital heart disease 96
Cyclic motility 52
Cytokines 141
D
Dexamethasone 123, 124
treatment 124
Diabetes
complication of 87
fetal lung maturation in women with 124
gestational 92
kinds of 121
overt 1
pregestational 1, 92
pregnancies complicated by 122, 124, 129
pregnant women with 123
type 1 14, 105, 139
type 2 112, 113, 136, 139, 144
Diabetes during pregnancy 25
type 1 14
Diabetes in pregnancy 23, 88, 99, 134
biometric measurements 33
classification 23
diagnosis 1
epidemiology 24
management of 15t, 28, 32
pathophysiology 2
physiology 23
postnatal long-term risks 6
prevalence 1
risk factors 2, 26
screening and diagnosis 26
significance 25
treatment 1
Diabetes mellitus 23, 32, 53, 117
adult-onset 92
in women 62
non-insulin-dependent 92
pregestational 24, 34, 92, 113
type 2 1, 114, 134
Diabetes-related congenital anomalies, obstetric ultrasound for 92
Diabetic female, neurological function in fetus of 52
Diabetic mother
congenital malformations in offspring of 113
fetuses of 49
health of 106
infants of 63, 65, 110
offspring of 105, 110, 111
Diabetic pregnancy 39
biochemical parameters, management of 64
causative mechanism, management of 63
fetal behavior in 46
malformations, management of 64
management of 62
newborns from 114
offspring from 108
poorly regulated 106f
respiratory pathology in neonates from 109
Diabetic pregnant patients, monitoring 39
role of ultrasound in 41b
Diabetic vascular disease 49
Diazoxide 111
DM See Diabetes mellitus
Ductus venosus 39
E
Encephalocele 77f
Endogenous glucocorticosteroids 121
Enzyme 141
Erythropoiesis 107
Estrogen 2
Exencephaly 76f
Eyelid and lip movements 49f
F
Facial alteration 51
Facial expression 48
Femoral hypoplasia
bilateral 93
unilateral 93
unusual facies syndrome 101
Femur 86f
Fetal abdomen 82f
Fetal activity, normal 46
Fetal brain
in first trimester 101f
normal development of 49
Fetal congenital malformation, role of ultrasound in diagnosis of 38b
Fetal face with eye 55f
Fetal head rotation and anteflexion movement 56f
Fetal hematocrit 39
Fetal hepatic artery 40
Fetal hyperglycemia 107
Fetal intelligent navigation echocardiography 37
Fetal liver perfusion 39
Fetal lung
maturation
influence 122
physiology processes in 121
maturity
analysis, quantitative ultrasound 130
evaluation of 129
testing of 129
Fetal macrosomia, causes of 138f
Fetal or neonatal death, risk of 140t
Fetal pulmonary maturation, acceleration of 122
Fetal spine, normal 95f
Fetus with iniencephaly 76f
Fetus with large part of brain herniating 76f
Fetus, artificial maturation of 121
Fingers movements 51
Flat fetal head 75f
Four-chamber heart 72f, 74f
Fractional limb volume 33, 34f, 35f
Free fatty acid, increased 115
Fulminant infection 126
G
Gallbladder 72
Gastrointestinal
anomalies 100
tract 80, 93
GDM See Gestational diabetes mellitus
Genital anomalies 93
Gestational age 51
Gestational diabetes 25, 63, 1, 111, 130
detection of 129, 130
diagnosis 9t
management of women with 128
mellitus 23, 24, 32, 49, 92, 105, 111, 124, 134-136
cesarean section rate 138
congenital anomalies 137
development of 105
fetal macrosomia 137
management of 143
perinatal death 139
preeclampsia 138
premature births 140
prevalence of 105f
problems in 3
range of diagnostic criteria for 27t
risk of 26
women with 113, 125
Glucocorticoid
action 122
receptors 121
treatment 128
Glucose
control, effects of lactation on 18
metabolism, dysfunction of 1
test 8, 10, 12
benefits of 7
single-step 9
two-step 9
tolerance test 8, 9
Glycemic control
effects on 125
level of 139
Glycemic index 143
Glycemic levels, elevation of 125
Glycemic status 125
Glycosylated hemoglobin blood concentrations 62
Great vessels, transposition of 69
Grimace 51
H
Hand and facial movements in fetus, types of 48t
Hand and head movements 48
Hand to face movements 51
Health and disease, developmental origins of 106
Hepatic artery Doppler
steps 41f
technique 41f
Holoprosencephaly 79, 79f
Human placental
growth hormone 2
lactogen, levels of 2
Hydronephrosis 81
Hyperactivity disorders, attention deficit 53, 116
Hyperbilirubinemia 3, 6, 17, 107
Hyperechoic kidneys 82, 84f
Hyperglycemia 25, 49
and adverse pregnancy outcome 12, 26
Hyperinsulinemia 107
Hypertension 5
incidence of 138
Hypertonicity 53
Hypertrophic cardiomyopathy 71, 110
Hypertrophic myocardiopathy 97, 98f
Hypertrophy of interventricular septum 98f
Hyperviscosity 3, 6, 107
Hypocalcemia 3, 17, 107
Hypoglycemia 3, 6, 107, 112
reactive 49
Hypoinsulinemia 141
Hypomagnesemia 17
Hypoplasia-unusual facies syndrome 102
Hypoplastic left heart syndrome 73, 110
Hypotonicity 53
Hypoxia, chronic 49
I
IADPSG See International Association of Diabetes and Pregnancy Study Groups
Idiopathic thrombocytopenic purpura 123
Infancy and childhood, effect during 53
Inflammatory bowel disease 123
Insulin
deficiency 23
infusion rate 127
determination of 127t
resistance 138
of pregnancy 141
physiological 1
Insulin-dependent
diabetes mellitus 92
diabetic women 128
organs 32
Insulinoma 114
Intelligence quotient, reduced 49
International Association of Diabetes and Pregnancy Study Groups 27
Intracranial translucency 99
Intrauterine growth restriction 4, 49, 65
Intravenous insulin, supplementary 129
Iron deficiency 49
Islet cell dysregulation syndrome 114
Isolated eye blinking 51
Isolated hand movement 51
Isolated head anteflexion 51
Isolated leg movement 51
IUGR See Intrauterine growth retardation
J
Jaundice 112
Juvenile-onset diabetes mellitus 92
K
Kabuki syndrome 110
KANET See Kurjak's antenatal neurodevelopmental test
Ketogenic diet 142
Ketosis and pregnancy 143b
Kidney 82f
absence of 80
congenital anomalies of 114
Kurjak's antenatal neurodevelopmental test 50, 51, 53
L
Lactic acidosis, increased 117
Left atrium, small 74f
Left ventricle, small 74f
Left ventricular outflow tract 71
Leptin 141
Leukomalacia, cystic periventricular 124
Lumbosacral myelomeningoceles 99f
M
Macrocystic dysplastic kidney 84f
Macrocystic renal dysplasia 82
Macrosomia 4, 32, 84, 107
Macrosomic baby 122
Maternal blood glucose levels 52
Maternal diabetes 116
mellitus 96
Maternal gestational diabetes 114
Maternal glucose
control, level of 123
levels 123
Maternal hyperglycemia 4
fetal effects of 107
neonatal effects of 107
Maternal insulin-dependent diabetes 63, 101
Maternal ketonuria in diabetic mothers 49
Maternal mortality rate 134
influencing 134
Meconium plug syndrome 65
Medicine, communications in 130
Metabolic acidosis 107
Metabolic syndrome 2, 3, 6-8, 26, 32, 106, 112, 113, 144
Metabolism during pregnancy 141
Metformin 114
effect of 143
Microalbuminuria, presence of 139
Microcystic renal dysplasia 84f
Multicystic dysplasia 82
Myelocele with neural placode flush 100f
Myocardial hypertrophy 107
N
National diabetes data group 27
NCD See Noncommunicable diseases
NDDG See National diabetes data group
Neonatal complications 25
hyperbilirubinemia 25
hypocalcemia 25
hypoglycemia 25
polycythemia 25
Neonatal hypocalcemia 6
Neonatal intensive care unit 109
Neonatal metabolic disorders 6
Neonate with fused both lower limbs 81f
Neural tube defects 64, 74, 98, 113, 137
Neurodegenerative diseases 2
Neurological derangements, higher risk of 49
Neurological function, assessment of 50
Neuronal migrational disorders 102
Neuropsychiatric disease 116
Newborns from diabetic pregnancies, inhospital care for 108
Noncommunicable disease 32, 111
Nondiabetic pregnancies 106
Normal pregnancy, fetal behavior in 46
NTD See Neural tube defects
Nutritional deprivation in pregnancy 140
fasting 141
starvation 140
O
Obese pregnant women, specific enzymatic changes in 141t
Obesity 135, 136
on metabolism during pregnancy, effect of 142
OGTT See Oral glucose tolerance test
Open spina bifida, posterior fossa in 100f
Oral glucose
challenge test 11t, 27
tolerance test 8, 9, 18
P
PA See Pulmonary artery
Pelvic kidneys, bilateral 93
Perinatal asphyxia 107, 114
PGDM See Pregestational diabetes mellitus
Phocomelic diabetic embryopathy 93
Phosphatidylglycerol 123
PIH See Pregnancy-induced hypertension
Placental corticotrophin-releasing hormone, levels of 141
Pneumocyte cells, type 2 123
Polycystic ovarian
disease 114
syndrome 6, 10, 26, 114
Polycythemia 3, 6, 17, 39, 107
Polyhydramnios 5, 84, 122
ultrasound assessment of 87
Postprandial hyperglycemia 141
Predominately subcutaneous insulin treatment 128
Preeclampsia 5
Pregestational diabetes, treatment of 114
Pregnancy
diagnosed during 106
intervention
before 144
during 142
obesity in 134
second trimester terminations of 63
Pregnancy-induced hypertension 49
Pregnant diabetic rats, streptozotocin- induced 123
Prenatal and postnatal growth 111
Prenatal glucocorticoid 122
Progesterone 2
Prolactin 2
Prophylactic metformin, use of 143
Proteins, biosynthesis of 122
Pulmonary artery 69, 96
origin of 70
Pulmonary compliance 122
Pulmonary trunk, origin of 71f
R
RDS See Respiratory distress syndrome
Renal
abnormalities 80
agenesis 93
pelvicalyceal system, dilated 83f
pelvis, bilateral dilated 82f
pyelectasis 81
Respiratory disorders 107
Respiratory distress syndrome 3, 63, 107, 109, 112, 122
risk of 129
Rh hemolytic disease 114
RVOT See Right ventricular outflow tract
S
Sacral agenesis 93
Septal hypertrophy 71
Shoulder dystocia 4, 13
Sirenomelia
in fetus 81f
in fused limbs 81f
Situs inversus 72
Skeletal abnormalities 84
Skin defect, large 77f
Small-for-gestational-age infants, incidence of 138
Somatostatin 2
Sphingomyelin 123
Spina bifida 75, 93
Spinal canal defect 75
large 77f
Spinothalamic tract 48
Spontaneous fetal movement 52
Structural cardiac defects 95
Synthetic corticosteroids 124
for antenatal therapy and prophylaxis 123
Systemic lupus erythematosus 123
T
Target sign 102f
Thumb, movement of 55f
Tocolytic drug 125, 127
Tolerate oral glucose test 11
Tongue expulsion 51
Transient tachypnea 109
Truncus arteriosus 70, 71f
Turner's syndrome 110
Ureter on left side, double 83f
Ureteric duplication 82
Urethral agenesis 93
Urinary tract 93
V
Vena cava, inferior 39, 72
Ventricular outflow tract, right 68f
Ventricular septal defect 65, 67f, 71f, 97
large 70f
Vertebral anomalies 93
VSD See Ventricular septal defect
W
Waste elimination 121
Women with
diabetes, management policy for 128
gestational diabetes, management policy for 128
preexisting diabetes, management policy for 127
World Health Organization 135
×
Chapter Notes

Save Clear


Diabetes in Pregnancy: Diagnosis and TreatmentChapter 1

Cihat Sen,
Murat Yayla,
Olus Api
 
INTRODUCTION
Gestational diabetes (GD) that is the one of most common medical complications of pregnancy is the dysfunction of glucose metabolism which develops in the second half of pregnancy and disappears when pregnancy ends.1 Dysfunction of glucose metabolism may have various levels. While diet is sufficient generally, some may need insulin.
Pregestational diabetic and diabetes noticed for the first time during the pregnancy were distinguished from the diabetes cases developing during pregnancy, and two different definitions were set as “gestational diabetes” and “overt diabetes” according to the common definition made by The International Association of Diabetes and Pregnancy Study Group (IADSPG), The World Health Organization (WHO), and The American Diabetes Association (ADA).2-4 In this case, “gestational diabetes” defines the change which really appears during pregnancy and is diagnosed at the second half of pregnancy by tests and developing in the presence of “pancreas which cannot deal with the diabetogenic changes” of pregnancy.5 The pregnancy itself is the condition of “physiological insulin resistance”. “Overt diabetes” defines the diabetes cases which have the metabolic processes at the early periods of pregnancy almost same with nongestational condition and identified even in the first trimester where insulin resistance is not clear yet. The cases which do not meet “overt diabetes” criteria in the tests performed during gestational period but not found to have a normal carbohydrate metabolism, either, are diagnosed as “gestational diabetes” and their follow-up and treatment are carried out accordingly.
 
PREVALENCE
The prevalence of GD is about 3–25% of pregnant women.6 The main reason for different GD incidence rates among the population investigated is the difference in the incidence rate of type 2 diabetes mellitus (DM) in the society.7 Also, maternal obesity increasing at young ages, decreased physical activity, increased consumption of convenience food, and advanced maternal age and race are other factors which have impact on prevalence.7 At the same time, the differences in GD screening models, the threshold values used, and diagnostic criteria create differences in GD prevalence. However, even though different methods and diagnostic criteria are used, it is definite that the prevalence of type 2 DM and also GD has increased in time highly, especially within last 20 years.5,82
 
PATHOPHYSIOLOGY AND RISK FACTORS
Endocrine and metabolic changes in pregnancy occur right after conception. The main purpose of these changes occurring in maternal metabolism is to provide sufficient nutrient and fuel to fetus.9 Particularly in the last trimester where fetal growth is the fastest and therefore fetal nutrition need is the highest, the changes in maternal carbohydrate and lipid metabolism become more distinct. During the pregnancy, plasma levels of lipolytic hormones increase and generally maternal fat use elevates, “glucose” is for the use of fetus basically.
Maternal insulin resistance begins at second trimester with the effect of metabolic and hormonal changes and becomes distinctive at third trimester. In this way, insulin resistance increases much more with the increase of the levels of human placental lactogen, human placental growth hormone, estrogen, progesterone, cortisol, prolactin, somatostatin, and probably tumor necrosis factor-alpha (TNF-α) that have diabetogenic effects. All these changes reach their peak level approximately at the 30 weeks of gestation. Insulin resistance which develops as a result of normal physiological changes during pregnancy is required for sufficient nutrition and growth of fetus.9 Since maternal pancreas cannot deal with this situation when increased insulin resistance is encountered, these physiological changes result in GD which is a pathological condition.5 In fact, pathophysiological mechanisms developing in the formation of GD show similarities substantially with type 2 DM. In both cases, a substantial increase occurs in the insulin resistance as the week of gestation advances and insulin response is not sufficient.
Risk factors for GD are defined and were asserted to perform glucose screening or diagnostic tests in pregnant women having these risk factors. Type 2 DM history in the family (especially in first degree relatives) is related to GD.10 Also history of GD in previous pregnancy is a risk factor.11 Another risk factor is obesity [body mass index (BMI) ≥30 kg/m2].10-12 It is remarkable that 60–80% of GD cases are obese. Also, GD risk increases with BMI.11 Cardiometabolic risk factors such as pregestational hypertension and borderline high blood pressure values were also associated with increased GD risk.12 Obesity is associated with inflammatory changes. There is an increase in inflammatory cytokines, especially in the levels of TNF-α, interleukin-6, nuclear factor-κB (NFκB), plasminogen activator inhibitor-1 and C-reactive protein.13 Glucose levels chronically increased with obesity cause the modification of building blocks such as nucleic acids and proteins into advanced glycation end products (AGE). The accumulation of AGE which is fast and higher than physiological levels causes permanent damages in the tissues. Today, AGE formation is held responsible in the physiopathology of many diseases in diabetes cases including neurodegenerative diseases, metabolic syndrome, and vasculopathy.14 As a respond to AGE formation, a series of inflammatory response is initiated with NFκB pathway, and the tissue damage created with the activation of T-cells and the release of inflammatory cytokines in particular results with vasculopathy and fibrosis.15,16 Therefore, the development of complications such as myocardial infarction, atherosclerosis, stroke, etc. is not a surprise in obesity and DM patients.16 The same mechanism may explain the appearance of vascular complications basically such as insufficient placentation, preeclampsia, IUGR, sudden infant death under poor conditions caused by chronic hyperglycemia as well as obesity during pregnancy.3
In the diabetes prevalence studies performed in Turkey, DM prevalence was found as 13.7% according to the results of TURDEP-II performed with the participation of 26,000 individuals who were 20 years old and above in 2010.17 Almost half of the cases in DM group consist of newly diagnosed cases. Diabetes prevalence varies according to the regions in Turkey. While Northern Anatolia Region has the lowest prevalence rate (14.5%), Eastern Anatolia Region has the highest prevalence rate (18.2%). Eastern Anatolia Region was found to be the region with the lowest awareness for diabetes as well as the region having the highest prevalence rate.17 Compared to TURDEP-I18 study performed in 1998, the results found by TURDEP-II prevalence study showed that the diabetes prevalence rate increased for 90% and obesity for 44% in Turkey.17 Another issue revealed by TURDEP-II study is that diabetes prevalence rate increased significantly in those who are in reproductive period.17
Considering the worldwide diabetes prevalence is about 8.4%.19 In the light of these data, our country is among the regions with the highest prevalence according to comparative worldwide diabetes prevalence studies. It is known that GD prevalence is high among those originated from South Asia, black Caribbean, and Middle East.
When planning GD screening program, the characteristics of the population under investigation are also important. For instance, only 10% of the population in the USA is evaluated within low risk group. Therefore, it is wise to perform tests on every pregnant woman instead of carrying out a risk-oriented screening in the USA.20 Besides, considering the risk factors mentioned earlier, there are few pregnant women left. Hence, it does not seem logical to perform screening based on risk factors.
 
Why Screening and Identifying Important?
Clinically identifying GD is significant basically for preventing gestational complications, improving fetal and neonatal outcomes, and to prevent its long-term effects on next generations. While some of the complications developing associated with GD appear in the early period, some of them are seen in the long-term. Preterm labor, macrosomia, birth trauma, and sudden infant death can be listed among the fetal complications associated with GD.21-23 Among the early period complications in the newborns of GD mothers, there are poly-cythemia, hyperviscosity, hypoglycemia, hypocalcemia, hyperbilirubinemia, and respiratory distress syndrome (RDS).24,25 Among the long-term complications, obesity, metabolic syndrome, type 2 DM and increase in hyperactivity prevalence were found in the infants of GD mothers.26,27 Preeclampsia risk, increased operative labor risk, and polyhydramnios can be listed among the maternal risks.28,29 Also, the risk for type 2 DM, metabolic syndrome, and coronary artery disease increased in the long-term in GD mothers.30,31
Identifying GD in the early period decreases preeclampsia risk for 40% and macrosomic infant risk for 50%. Additionally, shoulder dystocia and brachial plexus palsy risks decrease for 60%. Early detection of GD also decreases stillbirth risk.32
 
FREQUENT OBSTETRIC AND PERINATAL PROBLEMS IN GESTATIONAL DIABETES
It is known that the presence of chronic hyperglycemia ongoing especially in the last 4–6 weeks of gestation is associated with sudden fetal death associated with possible acidosis even in 4normal fetuses anatomically.33,34 Even in GD cases with well-controlled metabolism, fetal macrosomia, neonatal hypoglycemia, polycythemia, and jaundice risks increased although there is no increase in perinatal mortality.21 Also, cesarean section is recommended when estimated fetal weight is more than or equal to 4,500 g.1
 
Macrosomia
It is the most common complication seen in gestational diabetes. Maternal factors associated with macrosomia are hyperglycemia, mother being overweight, being obese during pregnancy (>18 kg), advanced maternal age, and multiparity.35,36 While the rate of women delivering baby over 4,500 g is 2% in the general obstetric population, it is 4% among women with GD diagnosis.37 It is reported that 20–30% of the infants of women with GD diagnosis but not undergoing treatment born above 4,000 g.38
Fetal growth rate increases particularly in the second half of pregnancy. Maternal hyperglycemia (postprandial hyperglycemia in particular) in this period causes fetal hyperinsulinemia and fetal growth is triggered. Macrosomic fetuses of diabetic pregnant women are different anthropometrically from the macrosomic fetuses of normal pregnant women. There is excessive fat accumulation in the shoulders and bodies of these fetuses. This increases the prevalence of shoulder dystocia, brachial plexus injuries, and clavicle fracture.39 Similarly, cephalopelvic disproportion resulted in cesarean section is more frequent. Macrosomia is closely associated with neonatal hypoglycemia in particular and other metabolic complications in diabetic pregnant women. Unexplained sudden intrauterine death near term and asymmetric septal hypertrophy causing cardiac ventricle dysfunction are more frequent in these infants.40
 
Shoulder Dystocia and Birth Trauma
Macrosomia causes increase in the prevalence of shoulder dystocia which may result in brachial plexus injury and clavicle fractures in newborns of patients with GD. The prevalence of shoulder dystocia is 6–10 times higher in the infants of diabetic mothers.1 Brachial plexus injuries may cause a permanent damage in 5–22% of the babies.41
 
Interventional and Cesarean Deliveries
The rates of interventional and cesarean deliveries have increased depending on macrosomia, intrauterine growth retardation (IUGR) and presentation anomalies. The rate of cesarean is even higher in macrosomic fetuses in cases where glucose control cannot be established adequately. As the diabetes control gets worse, the cesarean rate increases accordingly. The most significant factors here except fetal weight are the failure of labor induction and fetal asphyxia. Cesarean section is recommended in diabetic pregnancies with fetal weights estimated 4,500 g and above.1 Normal vaginal delivery is recommended in other cases, and applying cervical prostaglandin in cases where labor induction is required is the only logical method to choose.
Timing of delivery is also a problematic issue for diabetic pregnancies. In cases with pregestational diabetes where glucose is well controlled, planning delivery after 39 weeks is suitable.42 However, either with or without insulin, no safe delivery week has been determined to recommend in the perspective of evidence-based medicine for GD cases.1 Therefore, 39 weeks of gestation should be aimed as in cases with overt diabetes.5
The frequency of fetal well-being tests is quite controversial. In GD cases with well-controlled metabolism, each physician and clinic may decide according to their own practices. However, GD and pregestational diabetes cases with weak glycemic control are under risk in terms of fetal asphyxia and the tests showing fetal well-being should certainly be performed in this group. Tests showing fetal well-being can be begun between 28 weeks and 32 weeks according to the glycemic control medical complications (nephropathy, vasculopathy, etc.) of patients.
 
Hypertension—Preeclampsia
They develop particularly during the late periods of pregnancy. While the association between GD and preeclampsia is revealed, the responsible mechanisms are still unclear. It is considered that the endothelial dysfunction in such cases cannot produce prostacyclin (PGI2) sufficient enough to meet elevated angiotensin-2 and vasopressin. It is seen in 5–10% in all pregnancies. Preeclampsia is seen more frequently in diabetic pregnant women with vascular problems such as proteinuria in particular. The increase of perinatal mortality is 20 times higher than those with normal blood pressure and it is considered as the main reason for maternal and fetal loss. While the relationship of insulin resistance with high blood pressure and obesity was shown and this relationship was clearly defined in men and nonpregnant women, the relationship of glucose intolerance with the problems concurrent with hypertension in pregnant women could not be determined with so accurate borders.43 In the studies performed, mean artery blood pressures of patients whose GD is found in the early periods of pregnancy and requiring insulin treatment were higher than the patients with normal glucose tolerance and are regulated with diet. Also, there are authors claiming that pregnancy-induced hypertension is the clinical reflection of insulin resistance. The relationship between increasing glucose level and the severity of preeclampsia has been shown in the studies performed.44 This problem is also the main reason of the premature labor in diabetic pregnant women. Today, findings have been accumulating and it is considered that the insulin resistance has a role in the development of preeclampsia, at least partially. It can be also thought that treating insulin resistance with this mechanism will decrease preeclampsia risk and even other anti-inflammatory effects of balancing carbohydrate metabolism of insulin may be protective against the development of preeclampsia. In a meta-analysis including 11 randomized controlled studies, the effects of insulin and metformin treatment were compared and a significant decrease was found in the pregnancy-induced hypertension with metformin treatment. Also, no difference was found in terms of preeclampsia between the groups undergoing insulin or metformin treatment. Therefore, the activities of insulin and metformin were found similar on the prevalence of preeclampsia in terms of treatment activity.45
 
Polyhydramnios
Polyhydramnios is seen in about one-third of the diabetic pregnancies. In such case, pregnant women should definitely be evaluated in terms of fetal malformations (particularly for 6the malformations of central nervous system and gastrointestinal system). However, it is considered that the presence of polyhydramnios in diabetic cases does not cause an additional increase in perinatal morbidity or mortality.46
 
Neonatal Metabolic Disorders
The prevalence of hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, and hyperbilirubinemia of babies born from women with gestational diabetes.
 
Hypoglycemia
The incidence rate of hypoglycemia was found as 25–40%.47 The incidence rate of hypoglycemia was reported high also in mothers with well-controlled plasma glucose concentration.48 It is considered that intrapartum glycemic control in particular determines the hypoglycemia risk of newborn. If hypoglycemia is not detected and intervened on time, it may lead to seizure, coma, and brain damage. Therefore, glucose follow-ups should be monitored carefully following the delivery until good metabolic control of the neonate is accomplished.
 
Polycythemia and Hyperviscosity
It is seen in 5–10% of diabetic pregnant women. It is closely related with glycemic control. Due to the decrease in oxygenation, erythropoietin levels of the umbilical cords of infants of diabetic mothers are typically high and therefore the rate of polycythemia is increased in such infants.24 Polycythemia leads to increase in the prevalence of postnatal hyperbilirubinemia and this also causes the increase in phototherapy need.41 Another potential problem is the tissue damage and ischemia associated with hyperviscosity.6
 
Neonatal Hypocalcemia and Hyperbilirubinemia
Neonatal hypocalcemia is a problem seen almost in 50% of the infants of diabetic mothers. It usually appears in the first 3 days of life. The incidence of hyperbilirubinemia is two times higher than health pregnancies and found in 25% of the infants of diabetic mothers.6 Another reason is the preterm labor associated with diabetes.
 
POSTNATAL LONG-TERM RISKS
 
Long-term Risks in Terms of Mother
Diabetes develops in about half of the women with GD within 22–28 years in the future.1 How short will the diabetes develop depends on the personal risk factors. Risks such as ethnic group, obesity, age, and polycystic ovarian syndrome cause diabetes to develop faster. The possibility of developing type 2 DM in patients requiring insulin during pregnancy is higher.49 For example, diabetes develops within 5 years following the pregnancy in 60% of Latin American women.1
It was found in the studies performed that those with GD were under risk also in terms of metabolic syndrome, atherosclerosis, and cardiovascular dysfunction after postpartum third month.507
Hyperinsulinemia during pregnancy displays 30–50% decrease just after delivery. The decrease slowly continues within following 6–12 weeks. Blood glucose levels return to normal levels in the early postnatal period in most of the patients with GD. Therefore, evaluating patients between postpartum 6 weeks and 12 weeks in terms of glucose metabolism is very important for determining the risk for the development of type 2 DM within following 5–10 years and establishing patient follow-up strategy.51,52
 
Long-term Risks in Terms of Fetus
The investigators monitoring the infants of diabetic mothers for future diabetes development reported that diabetes develop in such infants 20 times more than the infants of nondiabetic mothers.42 Obesity prevalence also increased in these infants. The mechanisms of maternal diabetes leading to future obesity in fetus are not known clearly. In a prospective study comparing the infants of GD, type 1 DM, and nondiabetic pregnant women, it was found that more than one-third of the babies born from women with GD were overweight or obese when they reach at the age of 11 years. This rate was found to be two times higher than those delivered by type 1 DM or nondiabetic women.53,54 Also, as another important point of this study, it was found that the maternal obesity during early pregnancy period is the most significant factor determining the risk for infants of women with GD being overweight at 2, 8, and 11 years old (and therefore the insulin resistance at early period). It was reported that smoking during pregnancy is also associated with the risk for childhood obesity. This result was found independent from GD treatment and macrosomic birth.54 The results of this study are remarkable for revealing how the preventable reasons of obesity becoming a serious public health issue is important.
In the HAPO study, which is one of the most significant studies on GD performed, the effect of being obese on fetal birth weight was found to be an additional 174 g, it was 339 g in pregnant women who were GD.55
Four groups were created in a cohort study investigating the risk factors for metabolic syndrome (obesity, hypertension, dyslipidemia, and glucose intolerance) during childhood.27 The groups were macrosomic baby and normal glucose tolerance [LGA (large for gestational age) + control)], macrosomic baby and GD (LGA + GD), normal birth weight and normal glucose tolerance (AGA + control), and normal birth weight and GD [AGA (average for gestational age) + GD]. The development of insulin resistance during childhood was found 10 times higher in LGA + GD group. The risk of developing metabolic syndrome at any period was not found to be different in LGA and AGA control group, but it was found 3.6 times higher in LGA + GD group than AGA + GD group.
It was found in the studies performed that the children of women with pregestational and GD had higher rates of attention-deficit hyperactivity disorder and weaker motor functions during school ages. No change was observed in cognitive functions.6
 
Benefits of Glucose Tests
The purpose of screening tests during pregnancy is not to diagnose but to determine the group under risk. It is still controversial if it is necessary to carry out diabetes screening during 8pregnancy or not, if it should be done to all pregnant women or only those under risk, and which method will be used for these tests. However, current data with the evidence-based medicine perspective show us that performing screening and diagnostic tests for GD is very significant in order to identify GD and do appropriate management plans, to decrease early period neonatal and maternal morbidities such as macrosomia, shoulder dystocia and preeclampsia, and to determine metabolic syndrome and related risks on time which are expected for mother and infant in the long-term.
Screening and diagnostic tests performed in the second trimester are done according to preferred test or by drinking 75 g liquid containing glucose as a single step test or 50 g and then 100 g if necessary as a two-step test and then evaluating venous plasma blood sample. These tests have no serious maternal or fetal effects. Only certain patients may have problem for consuming hyperosmolar liquid (more distinct in 100 g glucose).5 Therefore, 75 g glucose tolerance test (GTT) is considered as diagnostic test at a single step.
When test results indicate GD, first the diet-exercise is planned according to the week of gestation and then medical treatment later if necessary. Also, the family should be informed about perinatal risks that are associated with GD and fetal monitorization is required in case of necessity and the increase of prenatal examination frequency.5 In a study in which the cases with and without screening were modeled, it was shown that performing the test in populations with high GD and type 2 DM prevalence was beneficial for both preventing type 2 DM and costs.44 Without any significant decrease in the number of patients which are required to be evaluated with laboratory screening method, not screening patients with low risk may lead to overlook some patients with GD.
 
Glucose Tests
Maternal venous plasma changes under normal conditions are as follows when performing GTT: preprandial blood glucose (PBG) is between 80 mg/dL and 90 mg/dL. Within approximately 4–5 minutes, the solution containing 75 g glucose is drunk and BG level increases up to 130–140 mg/dL within 30–40 minutes, it decreases slightly below PBG level within 120–150 minutes; at the end of 180 minutes, PBG level is reached.56,57 In the individuals with normal carbohydrate metabolism, normal glucose levels are reached within about 2 hours. These tests have no risk for fetuses.5
It is still debated which screening should be done for GD (screening everyone or risk-based approach) and which test should be used.58 The reason for this dispute is that there is no distinct definition in the world in terms of the criteria for screening everyone and it is not clear which glucose intolerance case will provide treatment benefit. At this point, screening test should be selected by considering the purposes of screening and cost-benefit balance.
There are publications stating that GD diagnosis is delayed and there are high false results which are about 10–20% by applying 100 g OGGT to those who had abnormal results from 50 g glucose test.59 There is difference of opinion on the threshold value of 50 g GTT. When threshold value is considered as 140 mg/dL, 3-hour oral glucose tolerance test (OGTT) is performed in 10–15% of cases and GD is detected in 20–40% of the cases who undergo diagnostic test. With 140 mg/dL threshold value, the sensitivity was calculated as 80% and specificity as 90%, and the diagnosis of approximately 20% of the cases are overlooked.599
Table 1.1   Sensitivity and specificity of the methods used in gestational diabetes diagnosis.60
Screening method
Sensitivity (%)
Specificlty (%)
Risk factors
50
66
Random glucose measurement
40
90
HbA1c
40
90
50 g GTT (1-hour 140 mg/dL
59
91
75 g OGTT
79
83
(GTT: Glucose tolerance test; OGTT: Oral glucose tolerance test).
In 10% of the cases, serum glucose level in GTT is between 130 mg/dL and 140 mg/dL. Therefore, when the threshold value is decreased to 130 mg/dL in GTT, the sensitivity of the test increases to 90; however, the number of patients referred to diagnostic tests increases for 60%. In a study conducted in 2002, the sensitivity and specificity values were identified for GD screening methods and these values were given in Table 1.1.60 Finally, ADA and ACOG (American College of Obstetricians and Gynecologists) recommend glucose threshold value in serum as 140 mg/dL.1,2
 
Two-Step Glucose Test
Threshold values checked in venous serum and evaluation of 50 g GTT are as below.1 No diagnostic test is required for 50 g GTT below 140 mg/dL. In this case, negative predictive value is about 85–90%. So, the risk for overlooking GD in glucose values below 140 mg/dL is 10–15%.1
If 50 g GTT is between 140 mg/dL and 180 mg/dL, diagnostic 3-hour 100 g OGTT is applied. GD diagnosis is established in case that two of the values are positive in 100 g OGTT: If PBG is above 95 mg/dL, 1-hour BG is above 180 mg/dL, 2-hour BG is above 155 mg/dL, 3-hour BG is above 140 mg/dL, and 50 g GTT is above 180 mg/dL, the patient is directly established GD diagnosis and the treatment is initiated.
 
Single-Step Glucose Test
In 2010, IADPSG (International Association of Diabetes and Pregnancy Study Group) recommended new criteria for GD diagnosis. These diagnoses criteria were determined with HAPO study where the results of multinational 25,000 pregnant women were investigated.61 New IADPSG criteria were mainly prepared by focusing on the perinatal risk of parameters which are above 90 percentile. Accordingly, it is recommended to check PBG and hemoglobin A1c (HbA1c) or spot blood glucose (sBG). If PBG is above 126 mg/dL and HbA1c is above 6.5% or sBG is above 200 mg/dL, it is recommended to consider it as overt diabetes and treat accordingly. If the results are not consistent with overt diabetes, but PBG is above 92 mg/dL yet below 126 mg/dL, it is recommended to treat by considering it as GD. If PBG is below 92 mg/dL, it is recommended to test with 75 g OGTT between 24 weeks and 28 weeks of gestation. The diagnosis criteria of 75 g OGTT can be listed as follows: If at least one of the values below is positive, it is consistent with GD diagnosis: PBG above 92 mg/dL, 1-hour BG above 180 mg/dL, and 2-hour BG above 153 mg/dL.10
 
Which Glucose Test should We Do?
The IADPSG criteria differ with the recommendation that performing screening in the first trimester according to the algorithms used previously and screening with 75 g OGTT again in the second trimester if the result is negative in the first one.2 ACOG recommends carrying out screening in the risk group during the first trimester. When IADPSG criteria were applied, the rate of diagnosed GD cases increased to 18% but they were not adopted by ACOG.1
Since there was no optimal approach for the diagnosis of gestational diabetes, National Institutes of Health (NIH) held a consensus meeting with the aim of determining the most appropriate diagnostic approach.32 The results of related 97 studies (6 randomized controlled studies, 63 prospective cohort studies, and 28 retrospective cohort studies) were investigated and continuous and positive relationship was found between increasing glucose values and macrosomia, and between primary cesarean rates and increasing glucose values at 75 g OGTT. 50 g OGTT has higher negative predictive value as well as suboptimal positive predictive values.
It was reported in a prospective randomized controlled study doing cost analysis by comparing single-step and two-step screening that two-step screening is more convenient for cost analysis.62 The cost difference being not so much, and applying diet-exercise program to a wider pregnancy group providing positive effects not only on glucose levels but also gestational outcomes should not be overlooked.
Since type 2 diabetes is frequently seen in Turkey, it can be tolerated easily and done at a single step and it is also a diagnostic test, applying 75 g OGTT based on single value positivity to all pregnant women should be addressed as the most appropriate approach.
 
To Whom and When to Apply Glucose Test?
In the United States of America, it is logical to screen each pregnant woman since they have at least one of the risk factors that may damage balancing carbohydrate metabolism during pregnancy in 90% of pregnant women.1 Also, there is no risk factor in about 20% of pregnant women found to have GD.5 As a result of the systematic review done by the United States Preventive Services Task Force (USPSTF), it was stated that it is required to screen everyone after 24 weeks of gestation, but it does not help to screen everyone during early gestation period and that it is more significant to perform risk-based screening during the first antenatal visit.61
If the patient has a risk factor for type 2 DM (obesity, BMI ≥30 kg/m2, history of GD or damaged glucose metabolism, polycystic ovarian syndrome, etc.), screening during the first prenatal visit would be a logical approach.
Performing PBG evaluation in the risk group during first antenatal visit and 75 g OGTT during 24–26 weeks of gestation if PBG is below 92 mg/dL would be more appropriate. If the first screening is negative or no screening is performed in the early period, the screening should be carried out at 24–28 weeks of gestation.5
There are some matters to consider when conducting GTTs (Table 1.2). It is significant to provide an environment close to basic physiological conditions in order to standardize tests and measurements and to rule out other factors.11
Table 1.2   Points to consider in oral glucose tolerance test.
  • The test should be carried out in the morning
  • Fasting is required for at least 8 hours and maximum 14 hours
  • Patient should be on diet for at least 3 days uninterruptedly (minimum 150 mg carbohydrate daily). If pregnant woman is on a diet poor for carbohydrate before the text, insulin response to the test is less than the expected and false positivity rate increases
  • During the text, pregnant woman should be in sitting position and should not make any effort
  • Pregnant woman should not smoke for 12 hours before the test
  • Patient should rest for 30 minutes before preprandial glucose measurement
  • After preprandial glucose measurement, patient should drink 75 g glucose solution within 5 minutes
 
What to Do in Pregnant Women Who Cannot Tolerate Oral Glucose Test?
Performing serial glucose measurement would be logical approach in order to rule out hyperglycemic conditions in pregnant women who cannot tolerate standard OGTT.5 In pregnant women who have risk factors for GD in particular and cannot tolerate screening tests, it is necessary to perform random PBG and postprandial BG measurements. This approach is also convenient for patients who underwent gastric bypass operation.5 According to the review of Coustan et al. GD risk is very low in pregnant women whose PBG is lower than 85 mg/dL at 24 weeks of gestation.61 However, additional tests and measurements are required in values above this value.5
HbA1c is significant for evaluating treatment activity rather than screening and it gives information about metabolic process for at least 60 days.
 
HbA1c
In the studies, a proper threshold value with good sensitivity and specificity during GD screening could not be found for HbA1c. In four different studies conducted on this matter, HbA1c threshold values were found 5.0, 5.3, 5.5, and 7.5, but no clear result was obtained for detecting GD according to these values.63-66 In the study of Agarwal et al. performed on 442 patients, it was concluded that HbA1c is a weak test for GD screening.63 The population size in the study of Uncu et al. was 42 pregnant women and it was stated that HbA1c did not provide any additional contribution.64 Consequently, HbA1C is not recommended as a screening test due to inconsistencies in the standardization, technical problems, lack of wide- availability and high-cost. However, it is accepted as the “golden standard” for the follow-up of glycemic control.
In regions where healthcare service cannot be provided sufficiently, checking PBG between 24 weeks and 28 weeks of gestation can be a practical approach. In a study conducted in China by compiling the data of 15 hospitals where 24,584 pregnant women were screened, it was reported that performing diagnostic 75 g OGTT on pregnant women whose PBG is 12between 79–90 mg/dL will reduce the requirement of 2-hour diagnostic test by half.65 However, when applying screening tests, a specific approach should be determined by considering the characteristics of population. It cannot be generalized in this study since ethnical characteristics affect type 2 DM prevalence and also different threshold values were used in the study conducted in China.67
 
May Glucose Tests be Harmful for Mother and Fetus?
In the studies performed, it was shown that consuming concentrated hyperosmolar glucose solutions for GD screening and diagnostic tests may cause gastrointestinal osmotic imbalance which results with gastric irritation, delay in gastric discharge, nausea, and vomiting in less number of patients.
In a study performed by Agarwal et al., it was reported that 9.8% of 5,142 pregnant women could not complete 100 g OGTT. The major reason for being unable to complete the test was the vomiting of pregnant women. In 2% of the cases, various reasons were found such as children of pregnant women drinking the solution, eating food during test, not giving blood at required times, and being unable to complete test in term of time.68 It was reported that OGTT has no side effects other than those stated earlier.5,69
 
2014 Cochrane Review: Different Results?
In the Cochrane70 review in 2014 few high quality evidences on the improvement of maternal and neonatal health by GD screening were found based on the data of 3,972 women and 4 studies (Bergus and Murphy, 1992; Murphy et al., 1994; Griffin et al., 2000; Martinez Collado et al., 2003) which were consistent with the criteria among 31 studies.71-74 These studies were carried out in limited regions. When thinking on GD risk and screening approach, the characteristics of the population investigated (such as ethnic group, nourishment habits, etc.) should be considered and interpreted accordingly. It would be useful to assess carefully these studies included in 2014 Cochrane review by considering their weak aspects and to remain distant towards the results and interpretations of this review in the current situation.
Since these four studies included in this meta-analysis have included only a particular group of pregnant population with GD, we would recommend further subgroup analysis with sufficient power in order to achieve a more definitive conclusion. Also, other studies are required for determining the efficacy of other methods (such as capillary blood sugar test, glycosuria, etc.) which can be used instead of GTTs that are applied simpler yet cannot be tolerated by some patients.70
 
HAPO Study: Why Important?
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study is an epidemiological research designed to seek an answer about how various levels of glucose intolerance affects fetal and perinatal outcomes during pregnancies. It is a study planned internationally and including 25,505 pregnant women from various ethnical groups. Its primary results were determined as macrosomia, primary cesarean frequency, neonatal hypoglycemia, and hyperinsulinemia. Preterm labor, preeclampsia, newborn intense care need, shoulder dystocia, birth trauma, 13and neonatal adiposity were considered as secondary results.75 A continuous relationship was found between glucose levels below maternal diabetes limits and perinatal outcomes such as birth weight and umbilical cord C-peptide levels. While there is no particular threshold glucose level in predicting gestational outcomes, it was found that there is a direct association with gestational outcomes and complications as preprandial or 1-hour and 2-hour glucose levels increase (even within normal limits). Even though the outcomes of this study are below overt diabetes levels, the more blood glucose levels are kept under control, the more it reflects positively to the gestational outcomes.
However, observing poor gestational outcomes also in pre- and postprandial blood glucose levels that we identified within “normal” levels make us consider that new threshold values should be used in screening models. In the light of the results of HAPO study, new IADPSG criteria were defined.76 While single positive value being sufficient for the diagnosis and also the threshold values being slightly lower increase the sensitivity in the new IADPSG criteria, the prevalence of diagnosed GD cases increases to 18%.1 These threshold values correspond to mean glucose levels where birth weight, umbilical cord C-peptide levels, and macrosomia risk increase 1.75 times. In cases established with GD diagnosis according to these threshold values, macrosomia, preeclampsia, and preterm labor risks increase 2 times. However, further studies are needed to get more information how gestational outcomes will improve or if they will improve or not depending on the treatment in GD cases diagnosed according to IADPSG criteria. It was observed that perinatal complications decreased from 4% to 1% in the study of Crowther et al. for randomized treatment activity on control group and the cases diagnosed with 75 g OGTT during 24–28 weeks. It was found that glucose control, diet, and treatment program with insulin in required cases decreased perinatal morbidity significantly.48 A similar randomized study was conducted by Landon et al. on a milder case group in 2009.77 In that study, 50 g and 100 g glucose tests were used during 24–31 weeks of gestation on pregnant group who had abnormal values in tests but the level of preprandial BG was below 95 g. While perinatal losses (no perinatal death case) and severe newborn complications did not decrease with the treatment program applied in this study, a particular improvement was observed in the rates of birth weight, shoulder dystocia, cesarean, and preeclampsia. Finding treatment activity even in mild cases with this study shows that glucose level and perinatal outcomes are directly associated even without a particular threshold value of HAPO study.75 While the rates of cases diagnosed with GD increased twice by using 75 g and single value seem as an advantage, they seem as an advantage assessing the results of Landon et al. study.77
The direct association between perinatal outcomes and glucose level found in HAPO study (also in low glucose level) shows the significance and efficiency of diet-exercise program. In this sense, applying 75 g and single value OGTT to all pregnant women doubles the rates of GD but it also helps to apply diet-exercise program to pregnant women and therefore to improve perinatal outcomes. Although its activity on short-term outcomes was revealed by the studies published by Crowther et al.48 and Landon et al.,77 there has been no study showing its activity on long-term outcomes. It will become clearer with further studies to be performed on the activity of this new diagnosis and treatment approach.
It was shown in a study investigating the effects of high pregestational maternal body mass index on gestational outcomes that pregestational BMI is related with more operative delivery and more neonatal problems.78 GD prevalence was found as 21.1% in the study of Göymen 14et al.79 It was claimed in the same study that there was no difference in terms of GD rates when two-step or single-step screening is performed.79 In a study investigating maternal serum leptin and malondialdehyde (MDA) levels in GD diagnosis and screening, it was reported that leptin, MDA, and HbA1c levels increased significantly in GD cases, and these tests were found to increase the specificity of the GD screening modalities.80 In another study comparing maternal serum adiponectin and leptin measurements in GD diagnosis and screening, it was shown that adiponectin was more sensitive but had equal specificity in the group which underwent 75 g OGTT. Adiponectin was found significantly low in the group which underwent two-step screening.81
In a study evaluating 50 g screening and 100 g OGTT results of 690 pregnant women in terms of fetal macrosomia, it was argued that the patients with 50 g screening result over 140 mg/dL should be followed up closely in terms of fetal macrosomia like the patients with GD even though their 100 g OGTT results are not positive.82 In another study investigating the etiological factors in macrosomic fetuses, maternal age being above 35, high parity, high average of maternal height, weight gained during pregnancy being over 12 kg, high level of HbA1c, presence of polyhydramnios in current pregnancy, and the medical history with macrosomic infant were considered as the factors increasing macrosomia risk in fetus.83
 
TYPE 1/TYPE 2 DIABETES DURING PREGNANCY
Diabetes is the disorder of carbohydrate metabolism affecting life considerably. It is a chronic disease leading long-term complications such as retinopathy, nephropathy, and vascular diseases. It is seen in 2–5% of women in England. While 5% of this group is type 2 DM, type 1 DM is 7.5% and GD is 87.5%. It is known that the rates of type 1 and type 2 diabetes gradually increase. Type 2 diabetes is frequently seen in Africa, Caribbean, South Asia, Middle East, and China in particular.6-8
Miscarriage, preeclampsia, and early labor are seen frequently in diabetic pregnant women (type 1 and type 2). Besides, it should be remembered that retinopathy may get worse during pregnancy. Postpartum compliance problems such as stillbirth, congenital anomalies, macrosomia, birth trauma, perinatal mortality, and hypoglycemia are seen more frequently.22,23,31
One of the first steps of making a successful follow-up in diabetic patients is to establish a good communication between healthcare professionals and patient. It is useful to provide detailed information on diabetes and pregnancy as well as delivering this information to patient in written. In this way, patient has a referring source when required. Diabetic (type 1 or type 2) pregnant women can be clinically taken care of as in Table 1.3.
 
CONCLUSION AND RECOMMENDATIONS
The 75 g OGTT at 24–28 weeks of gestation on routine base in low risk group is recommended for the diagnosis of gestational diabetes. The direct association between perinatal outcomes and glucose level, and also the significance and efficiency of diet-exercise program have been recently shown in many studies. In this sense, applying 75 g and single value OGTT to all pregnant women doubles the rates of GD but it also helps to apply diet-exercise program to pregnant women and therefore to improve perinatal outcomes.15
Table 1.3   Recommendation for the management of diabetes in pregnancy.
Before pregnancy:
  • Patient should be informed about the importance of regulating glucose level well before pregnancy and also maintaining this level after pregnancy. In this way, the awareness that it is possible to prevent miscarriage, congenital malformation, stillbirth, and newborn death should be raised
    • Significance of diet, weight, and exercise
    • Hypoglycemia developing during pregnancy
    • How nausea-vomiting during pregnancy may affect glucose control
    • How the condition of large for gestational age may increase birth trauma, labor induction, and cesarean possibilities
    • How it is important to manage the condition of diabetic retinopathy before (treating if necessary) and during pregnancy
    • The importance of maintaining glucose level well during labor in order to prevent newborn hypoglycemia and providing early lactation of infant after birth
    • Conditions which may develop and require special or intense care in infant after birth even temporarily.
  • It should be informed in detail to such patients beginning from adolescence period that an unplanned pregnancy would be an undesired condition and it is very significant to conduct a well-planned birth control and if it will be discontinued, to refer to doctor and make a pregestational plan
  • Diabetic patients planning pregnancy should be informed that:
    • Risks associated with diabetes during pregnancy is also associated with diabetes period
    • It is important to conduct conception until a well glucose control (HbA1c being below 6.1%) is provided
    • Glucose level targets, glucose monitoring, treatment options if necessary, and treatment options for problems associated with diabetes and pregnancy should be discussed
    • A closer cooperation is required during pregnancy and management plans such as emergency cases should be discussed in details
    • Diet should be arranged for those planning to get pregnant
    • Weight loss program should be applied and informed about its significance for those planning to get pregnant and have BMI above 27 kg/m2
    • It is important to have 5 mg/day folic acid certainly by those planning to get pregnant in order to decrease the risk for neural tube defect
    • It is very important to do glucose measurements by themselves and they should be recorded by times
    • Type 1 diabetics in particular have to do ketonuria check with sticks when their glucose levels elevate or when they do not feel well
Reliability of diabetic drugs during pregnancy:
  • They should be informed that metformin used alone or as a support for insulin is an effective drug to get glucose levels. Other diabetic drugs should be discontinued before pregnancy and insulin should be used instead
  • It should be known that it was not shown in clinical studies that rapid-acting insulin analogs (aspart or lispro) used during pregnancy have negative effects on fetus or newborn
16
  • It should be stated to those undergoing insulin treatment or planning to get pregnant that there is insufficient data on the use of long-acting insulin analogs during pregnancy and therefore NPH (neutral protamine Hagedorn) insulin has been still an option preferred
Treatment reliability of diabetic complications during pregnancy:
  • Angiotensin-converting enzyme inhibitors and angiotensin-2 receptor antagonists should be discontinued before pregnancy or they should be discontinued as soon as possible when pregnancy is detected. Instead, other alternative treatments should be performed
  • Statins should be discontinued as soon as possible when pregnancy is detected
Retina evaluation before pregnancy:
  • Diabetic patients are absolutely required to have retina examination before pregnancy (if it is not performed within last 6 months)
  • It is useful to perform this examination first by drop and then digital imaging
Renal examination before pregnancy:
  • It is significant to examine kidneys including microalbuminuria before discontinuing birth control. If creatinine is ≥120 or glomerular filtration rate is <45, it should be reevaluated after nephrology consultation
Glucose follow-up in gestation:
  • Where possible, preprandial glucose level should be kept about 65–95 mg/dL and 1-hour glucose below 140 mg/dL, and importance of these levels should be explained
  • Patients with overt diabetes using insulin should be informed about the possibility of hypoglycemia attacks during first trimester in particular and the precautions
  • The cases whose glucose levels cannot be managed despite insulin use should be explained that using insulin pump is another method
  • Conditions where diabetic ketoacidosis is in question should be evaluated in hospital immediately and they should be put under care
  • It should be explained that diabetic retinopathy does not inhibit vaginal labor
  • It should be explained to pregnant women with overt diabetes that they should visit for diabetes control with 1–2 weeks of interval
Gestational follow-up:
  • First examination: Explaining the importance of and teaching glucose control, detailed anamnesis check for diabetes, drugs used, retina/kidney assessment
  • Evaluating pregnancy at 7–9 weeks of gestation
  • 13–14 weeks of fetal anatomy and fetal ECHO examination, diabetes and gestational interactions, delivery and lactation and newborn information
  • Reevaluating if retinopathy or nephropathy is found
  • Fetal anatomy and fetal ECHO examination at 20–22 weeks of gestation
  • Fetal development and amniotic fluid examination at 28 weeks of gestation, recheck if retinopathy or nephropathy is not detected in the first examination
  • Fetal development and amniotic fluid check at 32 weeks of gestation
  • Informing about fetal growth and amniotic fluid examination at 36 weeks of gestation, delivery timing-method and delivery management, analgesia or anesthesia, labor and then hypoglycemia management, infant care after delivery, lactation and its effect on glucose control, and conception
17
  • Unless there is fetal growth retardation, it is not necessary to do fetal well-being test routinely in diabetic pregnant women before 38 weeks of gestation
  • Fetal well-being tests in pregnant woman with approaching delivery at 38 weeks and inducting labor or planning cesarean if necessary
  • Fetal well-being tests at 39 weeks of in gestational diabetes
  • Fetal well-being tests at 40 weeks of gestational diabetes
  • Fetal well-being tests at 41 weeks of gestational diabetes
Preterm labor:
  • Checking if diabetes constitutes contraindication for the administration of steroid or tocolysis (without using beta mimetics) if necessary
  • Additional insulin will be required if steroid is administered, and glucose check should be performed more strictly
Timing and management of delivery:
  • In cases with normal fetal growth, delivery can be done by labor induction after 38 weeks of gestation and if necessary, cesarean can be planned
  • If fetal macrosomia is in question, pregnant woman should be informed about the risks of vaginal delivery, labor induction, and cesarean
  • In diabetic pregnant women, it would be beneficial to carry out evaluation and inform in terms of anesthesia in third trimester
  • If general anesthesia is applied, it should be known that glucose check is required every 30 minutes and it should be monitored until the effect of anesthesia diminish after delivery
Managing labor:
  • Capillary glucose level should be checked every hour during labor and it should be kept at 75–125 mg/dL
  • Applying dextrose infusion as well as insulin as of the onset of labor
  • If glucose level cannot be maintained at 75–125 mg/dL also in other cases, applying insulin together with dextrose infusion
Newborn management:
  • Diabetic pregnant women should deliver in a hospital capable of newborn resuscitation for 24 hours
  • Babies of diabetic mothers should be kept near their mothers. If any clinical complication or abnormal finding develops, then they should be monitored under special or intense care conditions
  • Glucose control of the infants of diabetic mothers should be performed every 2–4 hours routinely and if there is any clinical finding, they should be controlled for polycythemia, hyperbilirubinemia, hypocalcemia and hypomagnesemia
  • If there is any cardiomyopathy finding including congenital cardiac anomaly or murmur, fetal ECHO should be carried out
  • Infants of diabetic mothers with following findings should be monitored in newborn intense care units:
    • Hypoglycemia with clinical finding
    • Respiratory distress
    • Cardiomyopathy or cardiac failure due to congenital cardiac anomaly
    • Newborn encephalopathy
18
    • Polycythemia finding (need for partial blood exchange)
    • Intravenous fluid need
    • Need for gavage
    • Need for intense phototherapy and bilirubin control
    • Those born before 34 weeks.
  • Each obstetrics clinic should have and provide written information form for preventing, identifying, and managing newborn hypoglycemia
  • Despite all kinds of efforts, if blood glucose level decreases below 36 mg in two consecutive measurements and if there is any abnormal clinical finding, gavage or intravenous dextrose application should be performed
  • If clinical finding of hypoglycemia is observed, glucose control should be performed immediately and dextrose should be rapidly administered intravenously
  • Newborns of diabetic mothers should be fed right after delivery (within 30 minutes) and then every 2–3 hours
  • Those with type 2 diabetes may continue using metformin but other drugs should not be used during lactation
  • The drugs for diabetic complications discontinued before and during pregnancy should be continued
Effects of lactation on glucose control:
  • Those with overt diabetes should decrease insulin doses right after delivery and they should be managed with frequent glucose control until the optimum level is obtained
  • Those with overt diabetes and using insulin should be informed that hypoglycemia risk will increase after delivery and they should keep available food or snack as they may be required before and after lactation
  • If those with gestational diabetes are using drug, they should discontinue their treatment right after delivery
Postpartum follow-up and information:
  • After delivery, those with overt diabetes should be referred to the clinic that they are followed up
  • The glucose levels with gestational diabetes after delivery should be checked before discharging
  • Those with gestational diabetes should be warned and informed about the risk for developing hypoglycemia
  • Those with gestational diabetes should be checked for weight during postpartum period, diet-exercise applications should be maintained and their preprandial glucose levels should be checked at 6 weeks (not OGTT)
  • Those with gestational diabetes should be warned and informed that they may be diabetic later. They should undergo preprandial blood glucose check or OGTT in advance when they plan pregnancy.
(OGTT: Oral glucose tolerance test)
Although its activity on short-term outcomes was revealed by the studies. There has been no study showing its activity on long-term outcomes. It will become clearer with further studies to be performed on the activity of this new diagnosis and treatment approach.
19
REFERENCES
  1. Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 137: Gestational diabetes mellitus. Obstet Gynecol. 2013;122:406–16.
  1. International Association of Diabetes and Pregnancy Study Groups Consensus Panel; Metzger BE, Gabbe SG, Persson B, Buchanan TA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676–82.
  1. World Health Organization. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy. Geneva: World Health Organization;  2013.
  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 Suppl 1:S81–90.
  1. Coustan DR, Jovanovic L. Diabetes mellitus in pregnancy: screening and diagnosis. In: Nathan DM, Greene MN, Barrs VA (Eds). 2014. [online] UpToDate website.  Available from: www.uptodate.com [Accessed July 2017].
  1. Moore TR, Hauguel-De Mouzon S, Catalano P. Diabetes in pregnancy. In: Creasy RK, Resnik R, Greene MF, et al (Eds). Creasy and Resnik's Maternal-fetal Medicine: Principles and Practice, 7th edition. Philadelphia, PA: Saunders-Elsevier;  2014. pp. 988–1021.
  1. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care. 2007;30 Suppl 2:S141–S6.
  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services;  2014.
  1. Petraglia F, D'Antona D. Maternal endocrine and metabolic adaptation to pregnancy. In: Lockwood CJ, Snyder PJ, Eckler K (Eds). 2014. [online] UpToDate website.  Available from: www.uptodate.com [Accessed July 2017].
  1. Solomon CG, Willett WC, Carey VJ, et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA. 1997;278:1078–83.
  1. Chasan-Taber L. Gestational diabetes: is it preventable? Am J Lifestyle Med. 2012;6:395–406.
  1. Hedderson MM, Darbinian JA, Quesenberry CP, et al. Pregravid cardiometabolic risk profile and risk for gestational diabetes mellitus. Am J Obstet Gynecol. 2011;205:55.e1–7.
  1. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab. 2000;11:212–7.
  1. Bao W, Min D, Twigg SM, et al. Monocyte CD147 is induced by advanced glycation end products and high glucose concentration: possible role in diabetic complications. Am J Physiol Cell Physiol. 2010;299:1212–9.
  1. Artunc-Ulkumen B, Pala HG, Pala EE, et al. Exenatide improves ovarian and endometrial injury and preserves ovarian reserve in streptozocin induced diabetic rats. Gynecol Endocrinol. 2015;31:196–201.
  1. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25:4–7.
  1. Satman I, Omer B, Tutuncu Y, et al.; TURDEP-II Study Group. Twelve years trends in the prevalence and risk factors of diabetes and prediabetes in Turkish adults. Eur J Epidemiol. 2013;28:169–80.
  1. Satman I, Yilmaz T, Sengül A, et al. Population-based study of diabetes and risk characteristics in Turkey: results of the Turkish diabetes epidemiology study (TURDEP). Diabetes Care. 2002;25:1551–6.
  1. International Diabetes Federation (IDF). Diabetes Atlas, 6th edition. Brussels, Belgium: International Diabetes Federation;  2013.
  1. Danilenko-Dixon DR, Van Winter JT, Nelson RL, et al. Universal versus selective gestational diabetes screening: application of 1997 American Diabetes Association recommendations. Am J Obstet Gynecol. 1999;181:798–812.

  1. 20 Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ. 2010;340:c1395.
  1. Jovanovic L, Knopp RH, Kim H, et al. Elevated pregnancy losses at high and low extremes of maternal glucose in early normal and diabetic pregnancy: evidence for a protective adaptation in diabetes. Diabetes Care. 2005;28:1113–7.
  1. Schwartz R, Grupposo PA, Petzold K, et al. Hyperinsulinemia and macrosomia in the fetus of the diabetic mother. Diabetes Care. 1994;17:640–8.
  1. Widness JA, Teramo KA, Clemons GK, et al. Direct relationship of antepartum glucose control and fetal erythropoietin in human type 1 (insulin-dependent) diabetic pregnancy. Diabetologia. 1990;33:378–83.
  1. Cordero L, Treuer SH, Landon MB, et al. Management of infants of diabetic mothers. Arch Pediatr Adolesc Med. 1998;152:249–54.
  1. Pettitt DJ, Lawrence JM, Beyer J, et al. Association between maternal diabetes in utero and age at offspring's diagnosis of type 2 diabetes. Diabetes Care. 2008;32:2126–30.
  1. Boney CM, Verma A, Tucker R, et al. Metabolic syndrome in childhood: association with birth weight, maternal obesity and gestational diabetes mellitus. Pediatrics. 2005;115:e290–6.
  1. Pettitt DJ, Knowler WC, Baird HR, et al. Gestational diabetes: infant and maternal complications of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care. 1980;3:458.
  1. Evers IM, de Valk HW, Visser GH. Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ. 2004;328:915.
  1. Landon MB, Mele L, Spong CY, et al. Eunice Kennedy Shriver National Institute of Child Health, and Human Development (NICHD) Maternal–Fetal Medicine Units (MFMU) Network. The relationship between maternal glycemia and perinatal outcome. Obstet Gynecol. 2011;117:218–24.
  1. Sibai BM, Caritis S, Hauth J, et al. Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol. 2000;182:364–9.
  1. National Institutes of Health consensus development conference statement: diagnosing gestational diabetes mellitus, March 4-6, 2013. Obstet Gynecol. 2013;122:358–69.
  1. Centers for Disease Control (CDC). Perinatal mortality and congenital malformations in infants born to women with insulin-dependent diabetes mellitus-United States, Canada, and Europe, 1940-1988. MMWR Morb Mortal Wkly Rep. 1990;39:363–5.
  1. Whitelaw B, Gayle C. Gestational diabetes. Obstet Gynaecol Reprod Med. 2011;21:41–6.
  1. Caughey AB. Gestational diabetes mellitus: obstetrical issues and management. In: Greene MF, Barss VA (Eds). 2014. [online] UpToDate website.  Available from: www.uptodate.com [Accessed July 2017].
  1. Hillier TA, Pedula KL, Vesco KK, et al. Excess gestational weight gain: modifying fetal macrosomia risk associated with maternal glucose. Obstet Gynecol. 2008;112:1007–14.
  1. Ales KL, Santini DL. Should all pregnant women be screened for gestational glucose intolerance? Lancet. 1989;1(8648):1187–91.
  1. Garner P, Okun N, Keely E, et al. A randomized controlled trial of strict glycemic control and tertiary level obstetric care versus routine obstetric care in the management of gestational diabetes: a pilot study. Am J Obstet Gynecol. 1997;177:190–5.
  1. McFarland MB, Trylovich CG, Langer O. Anthropometric differences in macrosomic infants in diabetic and nondiabetic mothers. J Matern Fetal Med. 1998;7:292–5.
  1. Kenzel W, Misselwitz B. Unexpected fetal death during pregnancy-a problem of unrecognized fetal disorders during antenatal care. Eur J Obstet Gynecol Reprod Biol. 2003;110 Suppl 1:86–92.
  1. Hollander MH, Paarlberg KM, Huisjes AJM. Gestational diabetes: a review of the current literature and guidelines. Obstet Gynecol Surv. 2007;62:125–39.
  1. Witkop CT, Neale D, Wilson LM, et al. Active compared with expectant delivery management in women with gestational diabetes: a systematic review. Obstet Gynecol. 2009;113:206–17.
  1. Berkowitz KM. Insulin resistance and preeclampsia. Clin Perinatol. 1998;25:873–85.

  1. 21 Yogev Y, Xenakis EM, Langer O. The association between preeclampsia and the severity of gestational diabetes: the impact of glycemic control. Am J Obstet Gynecol. 2004;191:1655–60.
  1. Li G, Zhao S, Cui S, et al. Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs. Arch Gynecol Obstet. 2015;292:111–20.
  1. Shoham I, Wiznitzer A, Silberstein T, et al. Gestational diabetes complicated by hydramnios was not associated with increased risk of perinatal morbidity and mortality. Eur J Obstet Gynecol Reprod Biol. 2001;100:46–9.
  1. Casey BM, Lucas MJ, MCIntire DD, et al. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol. 1997;90:869–73.
  1. Crowther CA, Hiller JE, Moss JR, et al. Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477–83.
  1. Tamas G, Kerenyi Z. Current controversies in the mechanisms and treatment of gestational diabetes. Curr Diab Rep. 2002;2:337–46.
  1. Coustan DR. Gestational diabetes mellitus: glycemic control and maternal prognosis. In: Nathan DM, Greene MN, Barrs VA (Eds). 2014. [online] UpToDate website.  Available from: www.uptodate.com [Accessed July 2017].
  1. Gaudier FL, Hauth JC, Poist M, et al. Recurrence of gestational diabetes mellitus. Obstet Gynecol. 1992;80:755–8.
  1. American Diabetes Association. 12. Management of diabetes in pregnancy. Diabetes Care. 2016;39 Suppl 1:S94–98.
  1. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care. 2002;25(10):1862–8.
  1. Boerschmann H, Pflüger M, Henneberger L, et al. Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabetes Care. 2010;33:845–9.
  1. McIntyre HD, Cruickshank JK, McCance DR, et al. HAPO Study Cooperative Research Group. The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care. 2012;35:780–6.
  1. Vasudevan DM, Sreekumari S, Vaidyanathan K. Regulation of blood glucose, insulin and diabetes mellitus. In: Vasudevan DM, Sreekumari S, Vaidyanathan K (Eds). Textbook of Biochemistry for Medical Student. Section C: Clinical and Applied Biochemistry, 7th edition. New Delhi: Jaypee Brothers Publishers;  2013. pp. 311–34.
  1. Paulev PE, Zubieta-Calleja. Blood glucose and diabetes. In: Paulev PE, Zubieta-Calleja G (Eds). New Human Physiology. Textbook in Medical Physiology and Pathophysiology: Essentials and Clinical Problems, 2nd edition. Copenhagen: University of Copenhagen;  2004.
  1. Coustan D, Nelson C, Carpenter MW, et al. Maternal age and screening for gestational diabetes: a population-based study. Obstet Gynecol. 1989;73:557–61.
  1. Ray R, Heng BH, Lim C, et al. Gestational diabetes in Singaporean women: use of the glucose challenge test as a screening test and identification of high risk factors. Ann Acad Med Singapore. 1996;25:504–8.
  1. Hana FW, Peters JR. Screening for gestational diabetes; past, present and future. Diabet Med. 2002;19:351–8.
  1. Moyer VA; U.S. Preventive Services Task Force. Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160:414–20.
  1. Meltzer SJ, Snyder J, Penrod JR, et al. Gestational diabetes mellitus screening and diagnosis: a prospective randomized controlled trial comparing costs of one-step and two-step methods. BJOG. 2010;117:407–15.
  1. Agarwal MM, Hughes PF, Punnose J, et al. Gestational diabetes screening of a multiethnic, high-risk population using glycated proteins. Diabetes Res Clin Pract. 2001;51:67–73.

  1. 22 Uncu G, Ozan H, Cengiz C. The comparison of 50 grams glucose challenge test, HbA1c and fructosamine levels in diagnosis of gestational diabetes mellitus. Clin Exp Obstet Gynecol. 1995;22:230–4.
  1. Agarwal MM, Dhatt GS, Punnose J, et al. Gestational diabetes: a reappraisal of HBA1c as a screening test. Acta Obstet Gynecol Scand. 2005;84:1159–63.
  1. Rajput R, Yogesh Yadav, Rajput M, et al. Utility of HbA1c for diagnosis of gestational diabetes mellitus. Diabetes Res Clin Pract. 2012;98:104–7.
  1. Zhu WW, Fan L, Yang HX, et al. Fasting plasma glucose at 24-28 weeks to screen for gestational diabetes mellitus: new evidence from China. Diabetes Care. 2013;36:2038–40.
  1. Agarwal MM, Punnose J, Dhatt GS. Gestational diabetes: problems associated with the oral glucose tolerance test. Diabetes Res Clin Pract. 2004;63:73–4.
  1. Linder K, Schleger F, Ketterer C, et al. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity. Diabetologia. 2014;57:1192–8.
  1. Tieu J, McPhee AJ, Crowther CA, et al. Screening and subsequent management for gestational diabetes for improving maternal and infant health. Cochrane Database Syst Rev. 2014;2:CD007222.
  1. Bergus GR, Murphy NJ. Screening for gestational diabetes mellitus: comparison of a glucose polymer and a glucose monomer test beverage. J Am Board Fam Pract. 1992;5:241–7.
  1. Murphy NJ, Meyer BA, O'Kell RT, et al. Carbohydrate sources for gestational diabetes screening. A comparison. J Reprod Med. 1994;39:977–81.
  1. Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diab Med. 2000;17:26–32.
  1. Martinez Collado JH, Alvarado Gay FJ, DaneL Beltran JA, et al. Glucose screening test in pregnant women. A comparison between the traditional glucose load and diet. Medicina Interna de Mexico. 2003;19:286–8.
  1. HAPO Study Cooperative Research Group. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Int J Gynecol Obstet. 2002;78:69–77.
  1. Lowe LP, Metzger BE, Dyer AR, et al.; HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations of maternal A1C and glucose with pregnancy outcomes. Diabetes Care. 2012;35:574–80.
  1. Landon MB, Spong CY, Thom E, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361:1339–48.
  1. Dündar Ö, Çiftpinar T, Tütüncü L, et al. The effects of the pre-pregnancy maternal body mass index on the pregnancy outcomes. Perinatal Journal. 2008;16:43–8.
  1. Göymen A, Altinok T, Uludag S, et al. The role of maternal serum adiponectin levels in screening and diagnosis of gestational diabetes mellitus. Perinatal Journal. 2008;16:49–55.
  1. Öncül M, Uludag S, Sen C, et al. The role of maternal serum leptin and malondialdehyde levels in screening and diagnosis of gestational diabetes mellitus. Perinatal Journal. 2009;17:1–35.
  1. Göymen A, Öncül M, Güralp O, et al. comparison of maternal serum adiponectin and leptin measurements in screening and diagnosis of gestational diabetes mellitus. Perinatal Journal. 2008;16:92–9.
  1. Keskin U, Ercan CM, Güngör S, et al. The effects of gestational diabetes mellitus screening and diagnostic tests on fetal macrosomia. Perinatal Journal. 2013;21:133–7.
  1. Akyol A, Talay H, Gedikbasi A, et al. The factors effective on the macrosomic deliveries of nondiabetic pregnant women. Perinatal Journal. 2014;22:83–7.