Archive
Search

You can search published articles.

Journal Information

Online ISSN
1305-3124

Established
1993

Editors-in-Chief
​Cihat Şen, ​Nicola Volpe

Editors
Cecilia Villalain, Daniel Rolnik, M. Mar Gil

Managing Editors
Murat Yayla

Statistics Editor
Resul Arısoy

Diabates in pregnancy: diagnosis and treatment. Practice Guidelines of Turkish Perinatology Society

Cihat Şen, Murat Yayla, Oluş Api, Elif Gül Yapar Eyi, Burcu Artunç Ülkümen

Article info

Diabates in pregnancy: diagnosis and treatment. Practice Guidelines of Turkish Perinatology Society. Perinatal Journal 2016;24(2):110-127 DOI: 10.2399/prn.16.0242009

Author(s) Information

Cihat Şen1,
Murat Yayla2,
Oluş Api3,
Elif Gül Yapar Eyi4,
Burcu Artunç Ülkümen5

  1. İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi, Perinatoloji Bilim Dalı, İstanbul
  2. Acıbadem International Hastanesi, Kadın Hastalıkları ve Doğum Kliniği, İstanbul
  3. Yeditepe Üniversitesi Tıp Fakültesi, Perinatoloji Bilim Dalı, İstanbul
  4. Dr. Zekai Tahir Burak Kadın Sağlığı Eğitim ve Araştırma Hastanesi, Ankara
  5. Celal Bayar Üniversitesi Tıp Fakültesi, Kadın Hastalıkları ve Doğum Anabilim Dalı, Manisa
Correspondence

Cihat Şen, İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi, Perinatoloji Bilim Dalı, İstanbul, [email protected]

Publication History

Manuscript Received: March 29, 2016

Manuscript Accepted: April 15, 2016

Earlyview Date: April 15, 2016

Conflicts of Interest

Conflicts of Interest: No conflicts declared.

While the routine approach for the diagnosis of gestational diabetes is 50-g glucose tolerance test and 100-g OGTT in cases of a positive screen, a new approach was brought to agenda after it was found in the study of Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study that there is a linear relationship between blood glucose levels and gestational outcomes, and this was found to be closely associated with each value increase. It was shown that the approach of establishing diagnosis based on a single value at once with 75-g OGTT which is recently common in clinical practice helps 18% of pregnant population to get diagnosed, and the diet and exercise following the diagnosis improved gestational outcomes and affected gestational outcomes even in obese cases without gestational diabetes. Pregestational obesity having effect on gestational outcomes even though there is no diagnosis of gestational diabetes and finding that keeping weight gain during pregnancy under control is improving gestational outcomes reveal the importance of this matter. While 75-g OGTT procedure based on single value increases the number of cases who are established the diagnosis of gestational diabetes compared to the two-step screening and diagnosis test, diet-exercise practice in cases with such diagnosis is a condition which keeps weight gain during pregnancy under control and also has a positive impact on gestational outcomes. Glycemia being above the desired range with 1–2 weeks of follow-up of the blood glucose will require medical treatment. This is an expected and desired target. Therefore, applying 75-g OGTT based on single value has become the new clinical practice and it is recommended. This clinical practice guideline was prepared by the Diabetes and Pregnancy Study Group of Turkish Perinatology Society.
Keywords

Diabetes, OGTT, pregnancy

This clinical practice guideline was prepared by the Diabetes and Pregnancy Study Group of Turkish Perinatology Society to clarify controversial issues in Turkey and facilitate clinical practice in the light of new scientific data obtained on pregnancy and diabetes recently.
Gestational diabetes (GD) which is one of the 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.
In the common definition made by IADSPG (The International Association of Diabetes and Pregnancy Study Group), WHO (The World Health Organization) and ADA (The American Diabetes Association), those who are pregestational diabetic and noticed during the pregnancy for the first time were distinguished from the diabetes cases developing during pregnancy, and two different definitions were set as “gestational diabetes” and “overt diabetes”.[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 non-gestational 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
About 3–25% of pregnant women are established with GD diagnosis.[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.[5,8]
Pathophysiology and Risk Factors
Together with pregnancy, endocrine and metabolic changes occur right after conception. The main purpose of these changes occurring in maternal metabolism is to provide sufficient nutrient 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 carbonhydrate and lipid metabolism become more distinct. During pregnancy, plasma levels of lipolytic hormones increase and generally maternal fat use elevates, “glucose” is for the use of fetus basically.[9] 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 hPL (human placental lactogen), hPGH (human placental growth hormone), estrogen, progesterone, CRH, cortisol, prolactin, somatostatin and probably tumor necrosis factor (TNF-a) 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 gestational diabetes are defined and it was asserted to perform glucose screening/diagnostic tests in pregnant women having these risk factors. These risk factors are listed in Table 1.
When planning gestational diabetes 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 above, there are few pregnant women left. Hence, it does not seem logical to perform screening based on risk factors.
Screening and Diagnosis: Why Important?
Clinically identifying gestational diabetes 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 complications in the newborns of GD mothers, there are polycythemia, hyperviscosity, hypoglycemia, hypocalcemia, hyperbilirubinemi, 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 normal fetuses anatomically.[33,34] Even in GD cases with well-controlled metabolism, fetal macromosia, neonatal hypoglycemia, polycytemia and jaundice risks increased although there is no increase in perinatal mortality.[21] Also, cesarean section is recommended when estimated fetal weight is ≥4500 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 4500 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 4000 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. 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 clavicular 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 restriction (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 4000 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.
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 poor glycemic control are under risk in terms of fetal asphyxia and the tests showing fetal well-being should certainly be performed in this group.[1] Tests showing fetal well-being can be begun between 28 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 gestational diabetes and preeclampsia is revealed, the responsible mechanisms are still unclear. It is considered that the endothelial dysfunction in such cases cannot produce prostacycline (PGI2) sufficient enough to meet elevated angiotensin-2 and vasopressine. 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 non-pregnant 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 gestational diabetes 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.[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 1/3 of the diabetic pregnancies. In such case, pregnant women should definitely be evaluated in terms of fetal malformations (particularly for the 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 diabates is increased.
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-up should be monitored carefully following the delivery until it is ensured that the metabolic control of the infant of diabetic mother.
Polycythemia and hyperviscosity 
It is seen in 5–10% of diabetic pregnant women and 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 25% of the infants of diabetic mothers.[6] Another reason is the preterm labor associated with diabetes.
Postnatal Long-term Risks
Long-term risks for mother
Diabetes develops in about half of the women with gestational diabetes 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 gestational diabetes were under risk also in terms of metabolic syndrome, atherosclerosis and cardiovascular dysfunction after postpartum third month.[50]
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 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 for 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 non-diabetic mothers.[42] Obesity prevalence is 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 non-diabetic pregnant women, it was found that more than 1/3 of the babies born from women with GD were overweight or obese when they reach 11-year-old. This rate was found to be two times higher than those delivered by Type 1 DM or non-diabetic 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-year-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 (Hyperglycemia and Adverse Pregnancy Outcome) study, which is one of the most significant studies on gestational diabetes 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, glucose intolerance) during childhood.[27] The groups were macrosomic baby and normal glucose tolerance (LGA+control), macrosomic baby and GD (LGA+GD), normal birth weight and normal glucose tolerance (AGA+control), and normal birth weight and GD (AGA+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.[27]
It was found in the studies performed that the children of women with pregestational and gestational diabetes 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 pregnancy 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 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 both for 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 glucose tolerance test: preprandial blood glucose (PBG) is between 80 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 glucose tolerance test. When threshold value is considered as 140 mg/dl, 3-hour 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.[59]
In 10% of the cases, serum glucose level in glucose tolerance test is between 130 and 140 mg/dl. Therefore, when the threshold value is decreased to 130 mg/dl in glucose tolerance test, 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 2.[60] Finally, ADA and ACOG 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 <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 140–180 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 >95 mg/dl, 1-hour BG is >180 mg/dl, 2-hour BG is >155 mg/dl, 3-hour BG is >140 mg/dl and 50-g GTT is ≥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 diagnosis criteria was 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 >90 percentile. Accordingly, it is recommended to check PBG and HbA1c or spot blood glucose (sBG). If PBG is >126 mg/dl and HbA1c is >6.5% or sBG is >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 ≥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 and 28 weeks of gestation. The diagnosis criteria of 75-g OGTT can be listed as follows: If PBG is below 126 mg/dl, it is consistent with overt diabetes. If at least one of the values below is positive, it is consistent with GD diagnosis: PBG ≥92 mg/dl, 1-hour BG ≥180 mg/dl and 2-hour BG ≥153 mg/dl.
Which Glucose Test Should We Do?
IADPSG criteria differ with the recommendation that performing screening in the first trimester according to the algorithms used previously and testing 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, NIH (National Institutes of Health) 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 costs.[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 have an affect on 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 USPSTF (States Preventive Services Task Force), 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 prenatal visit.[61]
If the patient has a risk factor for Type 2 DM (obesity, BMI ≥30 kg/m2, history of GD or impaired glucose metabolism, polycystic ovarian syndrome etc.), screening during the first prenatal visit would be a logical approach.[5] Performing PBG evaluation in the risk group during first antenatal visit and 75-g OGTT during 24–26 weeks of gestation if PBG is <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 glucose tolerance tests (Table 3). 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.
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 oral glucose tolerance test.[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]
Also, the methods such as glucose screening in urine and random blood glucose measurement were evaluated in terms of screening activity but no significant result was found. 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 performed, 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] For the reasons such as inconsistencies in the standardization of HbA1c, failure to measure at all clinics, technical problems and high costs, it does not seem convenient to use it in Turkey for screening purposes. 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 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 75g OGTT on pregnant women whose PBG is between 4.4 and 5.0 mmol/L (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?
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.[5] In a study performed by Agarwal et al., it was reported that 9.8% of 5142 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 above.[5,69]
2014 Cochrane Review: Different Results?
In the Cochrane[70] review performed in 2014 and investigated the impact of GD screening on improving the health of mother and neonate, few high quality evidences on the improvement of maternal and neonatal health by GD screening were found based on the data of 3972 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.
Consequently, it seen that further studies are required to determine which screening would be more appropriate. Since only a particular part of the pregnant population screened is established GD diagnosis, it is required to do sub-group analyses which are statistically powerful to do comparison and have sufficient population. Also, other studies are required for determining the activity of other methods (such as capillary blood sugar test, glucosuria etc.) which can be used instead of glucose tolerance tests that are applied simpler yet cannot be tolerated by some patients.[70]
HAPO Study: Why Important?
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 rate, neonatal hypoglycemia and hyperinsulinemia. Preterm labor, preeclampsia, newborn intensive care unit, shoulder dystocia, birth trauma and neonatal adiposity were considered as secondary results.[75] A continuous relationship was found between glucose levels (even 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 is 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 increase to 18%.[1] These threshold values correspond to mean glucose levels where birth weight, umbilical cord C-peptide levels and macrosomia risk increase for 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.’s study.[77]
The direct association between perinatal outcomes and glucose level found in HAPO study (also in low glucose level) show 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 gestational diabetes 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.
What Should We Recommend to Our Patients in Terms of Glucose Test?
As Perinatal Medicine Foundation and Turkish Perinatology Society, we have tried to establish a screening model for GD screening in our country within the perspective of evidence-based medicine. In Turkey, single-step 75-g diagnostic test seems more appropriate in terms of costs and patient compliance. Considering GD complications in particular, diagnosing under the light of our current information in order to protect fetus and mother from these complications is an evidence-based and scientific approach.
Studies on this Subject in Turkey
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 et al.[79] It was claimed in the same study that there was no different 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, but the findings found was increasing the specificity of the tests performed during the GD screening.[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 gestational diabetes 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 gestational diabetes 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 preterm delivery 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.
Perinatal Medicine Foundation and Turkish Perinatology Society emphasize and recommend that the practices listed in Table 4 are significant to obtain good perinatal outcomes in cases with overt diabetes and pregnancy (Recommendations 1–7).
References
  1. Committee on Practice Bulletins--Obstetrics. Practice Bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol 2013; 122:406–16. [PubMed] [CrossRef

  2. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–82.  [PubMed] [CrossRef

  3. World Health Organization. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy. Geneva: World Health Organization; 2013.

  4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37 Suppl 1:S81–90. [PubMed] [CrossRef

  5. Coustan DR, Jovanovic L. Diabetes mellitus in pregnancy: screening and diagnosis. In: Nathan DM, Greene MN, Barrs VA, editors. UpToDate [Internet]. Waltham, Mass.: UpToDate; 2014 [cited December 11, 2014]. Available from: www.uptodate.com

  6. Moore TR, Hauguel-De Mouzon S, Catalano P. Diabetes in pregnancy. In: Creasy RK, Resnik R, Greene MF, Iams JD, Lockwood CJ, Moore TR, editors. Creasy and Resnik’s maternal-fetal medicine: principles and practice. 7th ed. Philadelphia, PA: Saunders-Elsevier; 2014. p. 988–1021.

  7. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care 2007;30 Suppl 2:S141–S6. [PubMed] [CrossRef

  8. 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.

  9. Petraglia F, D’Antona D. Maternal endocrine and metabolic adaptation to pregnancy. In: Lockwood CJ, Snyder PJ, Eckler K, editors. UpToDate [Internet]. Waltham, Mass.: UpToDate; 2014 [cited January 06, 2014]. Available from: www.uptodate.com

  10. Solomon CG, Willett WC, Carey VJ, Rich-Edwards J, Hunter DJ, Colditz GA, et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 1997;278:1078–83. [PubMed] [CrossRef

  11. Chasan-Taber L. Gestational diabetes: is it preventable? American Journal of Lifestyle Medicine 2012;6:395–406. [CrossRef

  12. Hedderson MM, Darbinian JA, Quesenberry CP, Ferrara A. Pregravid cardiometabolic risk profile and risk for gestational diabetes mellitus. Am J Obstet Gynecol 2011;205:55.e1–7. [PubMed] [CrossRef

  13. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000;11:212–7. [PubMed] [CrossRef

  14. Bao W, Min D, Twigg SM, Shackel NA, Warner FJ, Yue DK, 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. [PubMed] [CrossRef

  15. Artunc-Ulkumen B, Pala HG, Pala EE, Yavasoglu A, Yigitturk G, Erbas O. Exenatide improves ovarian and endometrial injury and preserves ovarian reserve in streptozocin induced diabetic rats. Gynecol Endocrinol 2015;31:196–201. [PubMed] [CrossRef

  16. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004;25:4–7. [PubMed] [CrossRef

  17. Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S, Dinccag N, Karsidag K, et al.; TURDEP-II Study Group. Twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in Turkish adults. Eur J Epidemiol 2013;28:169– 80. [PubMed] [CrossRef

  18. Satman I, Yilmaz T, Sengül A, Salman S, Salman F, 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. [PubMed] [CrossRef

  19. International Diabetes Federation (IDF). Diabetes atlas. 6th ed. Brussels, Belgium: International Diabetes Federation; 2013.

  20. Danilenko-Dixon DR, Van Winter JT, Nelson RL, Ogburn PL Jr. Universal versus selective gestational diabetes screening: application of 1997 American Diabetes Association recommendations. Am J Obstet Gynecol 1999;181:798–812. [PubMed] [CrossRef

  21. Horvath K, Koch K, Jeitler K, Matyas E, Bender R, Bastian H, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ 2010;340:c1395. [PubMed] [CrossRef

  22. Jovanovic L, Knopp RH, Kim H, Cefalu WT, Zhu XD, Lee YJ, 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. [PubMed] [CrossRef

  23. Schwartz R, Grupposo PA, Petzold K, Brambilla D, Hiilesmaa V, Teramo KA. Hyperinsulinemia and macrosomia in the fetus of the diabetic mother. Diabetes Care 1994;17:640–8. [PubMed] [CrossRef

  24. Widness JA, Teramo KA, Clemons GK, Voutilainen P, Stenman UH, McKinlay SM, et al. Direct relationship of antepartum glucose control and fetal erythropoietin in human type 1 (insulin-dependent) diabetic pregnancy. Diabetologia 1990;33:378–83. [PubMed] [CrossRef

  25. Cordero L, Treuer SH, Landon MB, Gabbe SG. Management of infants of diabetic mothers. Arch Pediatr Adolesc Med 1998;152:249–54. [PubMed] [CrossRef

  26. Pettitt DJ,  Lawrence JM, Beyer J, Hillier TA, Liese AD, Mayer-Davis B, et al. Association between maternal diabetes in utero and age at offspring’s diagnosis of type 2 diabetes. Diabetes Care 2008;32:2126–30. [PubMed] [CrossRef

  27. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity and gestational diabetes mellitus. Pediatrics 2005;115:e290–6. [PubMed] [CrossRef

  28. Pettitt DJ, Knowler WC, Baird HR, Bennett PH. Gestational diabetes: infant and maternal complications of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care 1980;3:458–64. [PubMed] [CrossRef

  29. 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. [PubMed] [CrossRef

  30. Landon MB, Mele L, Spong CY, Carpenter MW, Ramin SM, Casey B, 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. [PubMed] [CrossRef

  31. Sibai BM, Caritis S, Hauth J, Lindheimer M, VanDorsten JP, MacPherson C, 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. [PubMed] [CrossRef

  32. National Institutes of Health consensus development conference statement: diagnosing gestational diabetes mellitus, March 4-6, 2013. Obstet Gynecol 2013;122:358–69. [PubMed] [CrossRef

  33. 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 990;39:363–5. [PubMed

  34. Whitelaw B, Gayle C. Gestational diabetes. Obstet Gynaecol Reprod Med 2011;21:41–6. [CrossRef

  35. Caughey A. Gestational diabetes mellitus: obstetrical issues and management. In: Greene MF, Barss VA, editors. UpToDate [Internet]. Waltham, Mass.: UpToDate; 2014 [cited December 15, 2014]. Available from: www.uptodate.com

  36. Hillier TA, Pedula KL, Vesco KK, Schmidt MM, Mullen JA, LeBlanc ES, et al. Excess gestational weight gain: modifying fetal macrosomia risk associated with maternal glucose. Obstet Gynecol 2008;112:1007–14. [PubMed] [CrossRef

  37. Ales KL, Santini DL. Should all pregnant women be screened for gestational glucose intolerance? Lancet 1989;1(8648):1187–91. [PubMed] [CrossRef

  38. Garner P, Okun N, Keely E, Wells G, Perkins S, Sylvain J, 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. [PubMed] [CrossRef

  39. McFarland MB, Trylovich CG, Langer O. Anthoropometric differences in macrosomic infants in diabetic and nondiabetic mothers. J Matern Fetal Med 1998;7:292–5. [PubMed] [CrossRef

  40. 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. [PubMed] [CrossRef

  41. Hollander MH, Paarlberg KM, Huisjes AJM. Gestational diabetes: a review of the current literature and guidelines. Obstet Gynecol Surv 2007;62:125–39. [PubMed] [CrossRef

  42. Witkop CT, Neale D, Wilson LM, Bass EB, Nicholson WK. Active compared with expectant delivery management in women with gestational diabetes: a systematic review. Obstet Gynecol 2009;113:206–17. [PubMed] [CrossRef

  43. Berkowitz KM. Insulin resistance and preeclampsia. Clin Perinatol 1998;25:873–85. [PubMed

  44. Yogev Y, Xenakis EM, Langer O. The association betvveen preeclampsia and the severity of gestational diabetes: the impact of glycemic control. Am J Obstet Gynecol 2004;191: 1655–60. [PubMed] [CrossRef

  45. Li G, Zhao S, Cui S, Li L, Zu Y, Li Y. Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs. Arch Gynecol Obstet 2015; 292:111–20. [PubMed] [CrossRef

  46. Shoham I, Wiznitzer A, Silberstein T, Fraser D, Holcberg G, Katz M, 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. [PubMed] [CrossRef

  47. Casey BM, Lucas MJ, MCIntire DD, Leveno KJ. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90: 869–73. [PubMed

  48. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; 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. [PubMed] [CrossRef

  49. Tamas G, Kerenyi Z. Current controversies in the mechanisms and treatment of gestational diabetes. Curr Diab Rep 2002;2:337–46. [PubMed] [CrossRef

  50. Coustan DR. Gestational diabetes mellitus: glycemic control and maternal prognosis. In: Nathan DM, Greene MN, Barrs VA, editors. UpToDate [Internet]. Waltham, Mass.: UpToDate; 2014 [cited January 15, 2015]. Available from: www.uptodate.com

  51. Gaudier FL, Hauth JC, Poist M, Corbett D, Cliver SP. Recurrence of gestational diabetes mellitus. Obstet Gynecol 1992;80:755–8. [PubMed

  52. American Diabetes Association. 12. Management of diabetes in pregnancy. Diabetes Care 2016;39 Suppl 1:S94–98. [PubMed] [CrossRef

  53. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862–8. [PubMed] [CrossRef

  54. Boerschmann H, Pflüger M, Henneberger L, Ziegler AG, Hummel S. Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabetes Care 2010;33:845–9. [PubMed] [CrossRef

  55. McIntyre HD, Cruickshank JK, McCance DR, Dyer AR, Metzger BE, 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. [PubMed] [CrossRef

  56. Vasudevan DM, Sreekumari S, Vaidyanathan K. Regulation of blood glucose, insulin and diabetes mellitus. In: Textbook of biochemistry. Section C: Clinical and applied biochemistry. 7th ed. New Delhi: Jaypee Brothers Publishers; 2013. p. 311–34.

  57. Paulev P-E, Zubieta-Calleja G. New human physiology. Textbook in medical physiology and pathophysiology: essentials and clinical problems [Internet]. 2nd ed. Copenhagen: University of Copenhagen; 2004. Chapter 27, Blood glucose and diabetes; [cited 2015 Jan 15]. Available from: http://www.zuniv.net/physiology/ book/chapter27.html

  58. Coustan D, Nelson C, Carpenter MW, Carr SR, Rotondo L, Widness JA. Maternal age and screening for gestational diabetes: a population-based study. Obstet Gynecol 1989;73: 557–61. [PubMed

  59. Ray R, Heng BH, Lim C, Ling SL. 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. [PubMed

  60. Hana FW, Peters JR. Screening for gestational diabetes; past, present and future. Diabet Med 2002;19:351–8. [PubMed] [CrossRef

  61. 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. [PubMed] [CrossRef

  62. Meltzer SJ, Snyder J, Penrod JR, Nudi M, Morin L. Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one-step and two-step methods. BJOG 2010;117:407–15. [PubMed] [CrossRef

  63. Agarwal MM, Hughes PF, Punnose J, Ezimokhai M, Thomas L. Gestational diabetes screening of a multiethnic, high-risk population using glycated proteins. Diabetes Res Clin Pract 2001;51:67–73. [PubMed] [CrossRef

  64. 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. [PubMed

  65. Agarwal MM, Dhatt GS, Punnose J, Koster G. Gestational diabetes: a reappraisal of HBA1c as a screening test. Acta Obstet Gynecol Scand 2005;84:1159–63. [PubMed] [CrossRef

  66. Rajput R, ogesh Yadav, Rajput M, Nanda S. Utility of HbA1c for diagnosis of gestational diabetes mellitus. Diabetes Res Clin Pract 2012;98:104–7. [PubMed] [CrossRef

  67. Zhu WW, Fan L, Yang HX, Kong LY, Su SP, Wang ZL, 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. [PubMed] [CrossRef

  68. Agarwal MM, Punnose J, Dhatt GS. Gestational diabetes: problems associated with the oral glucose tolerance test. Diabetes Res Clin Pract 2004;63:73–4. [PubMed] [CrossRef

  69. Linder K, Schleger F, Ketterer C, Fritsche L, Kiefer-Schmidt I, Hennige A, et al. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity. Diabetologia 2014;57:1192–8. [PubMed] [CrossRef

  70. Tieu J, McPhee AJ, Crowther CA, Middleton P. Screening and subsequent management for gestational diabetes for improving maternal and infant health. Cochrane Database Syst Rev 2014;2:CD007222. [PubMed] [CrossRef

  71. 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. [PubMed

  72. Murphy NJ, Meyer BA, O’Kell RT, Hogard ME. Carbohydrate sources for gestational diabetes screening. A comparison. J Reprod Med 1994;39:977–81. [PubMed

  73. Griffin ME, Coffey M, Johnson H, Scanlon P, Foley M, Stronge J, 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. [PubMed] [CrossRef

  74. Martinez Collado JH, Alvarado Gay FJ, DaneL Beltran JA, Gonzalez Martinez E. Glucose screening test in pregnant women. A comparison between the traditional glucose load and diet. Medicina Interna de Mexico 2003;19:286–8.  

  75. HAPO Study Cooperative Research Group. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Int J Gynecol Obstet 2002;78:69–77. [PubMed] [CrossRef

  76. Lowe LP, Metzger BE, Dyer AR, Lowe J, McCance DR, Lappin TR, 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. [PubMed] [CrossRef

  77. Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, 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. [PubMed] [CrossRef

  78. Dündar Ö, Çiftpınar T, Tütüncü L, Ergür AR, Atay MV, Müngen E. The effects of the pre-pregnancy maternal body mass index on the pregnancy outcomes. Perinatal Journal 2008;16:43–8.

  79. Göymen A, Altınok T, Uludağ S, Şen C, Öçer F, Uzun H, et al. The role of maternal serum adiponectin levels in screening and diagnosis of gestational diabetes mellitus. Perinatal Journal 2008;16:49–55.

  80. Öncül M, Uludağ S, Şen C, Göymen A, Uzun H, Güralp O, 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.

  81. Göymen A, Öncül M, Güralp O, Şen C, Uludağ S, Kanza Gül D, et al. comparison of maternal serum adiponectin and leptin measurements in screening and diagnosis of gestational diabetes mellitus. Perinatal Journal 2008;16:92–9.

  82. Keskin U, Ercan CM, Güngör S, Karaşahin K, Ergün A, Öztürk M, et al. The effects of gestational diabetes mellitus screening and diagnostic tests on fetal macrosomia. Perinatal Journal 2013;21:133–7. [CrossRef

  83. Akyol A, Talay H, Gedikbaşı A, Ark C, Ülker V, Özdemir Ç. The factors effective on the macrosomic deliveries of non-diabetic pregnant women. Perinatal Journal 2014;22:83–7. [CrossRef

  84.  
File/Dsecription
Table 1.
Risk factors for gestational diabetes.
Table 2.
Sensitivity and specificity of the methods used in GD diagnosis.[60]
Table 3.
Points to consider in OGTT.
Table 4.
Pregnancy and diabetes management.
Recommendation 1.
Informing each pregnant woman about pregnancy and diabetes
Recommendation 2.
Recommendations for gestational diabetes diagnosis
Recommendation 3.
Risk factors for gestational diabetes
Recommendation 4.
Diagnosis in gestational diabetes
Recommendation 5.
Detailed information and education stated below should be provided to pregnant women established with gestational diabetes on diet-exercise-medical treatment
Recommendation 6.
Follow-up during pregnancy
Recommendation 7.
Treatment in gestational diabetes