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

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).

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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