Treatment of Gestational Diabetes

Management of gestational diabetes mellitus (GDM) should consider both the maternal, fetal, and neonatal effects of the disease, line of treatment, and physiological changes during pregnancy. Women with GDM are classified into two categories according to their fasting blood glucose levels. Dietary control is mandatory in both classes, and the addition of pharmacological agents in those with fasting and 2-h postprandial plasma glucose levels <95 and 120 mg/dL is controver-sial (American College of Obstetricians and Gynecologists, 2013). Individualization of the diet in GDM according to women weight and height is recommended by the American Diabetes Association (ADA), and restriction of carbohydrate to a level that maintains normal glucose level is mandatory with individualization of the caloric intake according to women BMI and weight gain during pregnancy.


Introduction
The main aim of treatment of gestational diabetes is to prevent fetal, maternal, and neonatal complications.A randomized controlled trial which involved 1000 women with GDM showed that treatment of GDM is associated with the reduction of all neonatal complications, namely, birth injuries, shoulder dystocia, and perinatal morbidity and mortality.Treatment also reduced the rate of development of preeclampsia from 18 to 12% and the rate of large for gestational age (LGA) from 22 to 13% [1].Even in women with mild GDM, treatment reduced the rate of LGA, the mass of neonatal fat, shoulder dystocia, cesarean section, and hypertensive disorders associating pregnancy [2,3].
Improving the pregnancy outcome in women with GDM can be achieved through maintenance of fasting blood sugar levels <95 mg/dl (5.3 mmol/L), 1-h postprandial blood sugar <140 mg/dl (7.8 mmol/L), and 2-h postprandial blood sugar <120 mg/dl as recommended by both the American College of Obstetricians and Gynecologists (ACOG) and American Diabetes Association [4].
The treatment of GDM starts with dietary modifications along with particular nutritional approaches [5][6][7] combined with exercise [8,9].If this combination failed to maintain the needed glucose levels, pharmacological treatment starts, regardless of the lines used for treatment, proper monitoring of maternal health, fetal condition, and blood sugar levels.

Dietary modifications
Dietary counseling should be individualized according to women weight and height [10] through a registered dietitian [11].
JSOG committee on nutrient and metabolism problems described a caloric intake of 25-30 kcal/kg (+150 Kcal for the first half and + 350 kcal for the second half of pregnancy) [12].
The Ministry of Health and Welfare recommended a caloric intake of 25-30 kcal/kg (+ 50,250 and 450 kcal for the first, second, and third trimester, respectively) [13].
The ideal diet components are not yet determined.However excessive weight gain with postprandial hyperglycemia is commonly associated with diet that included 50-60% of carbohydrate.ACOG recommended the limitation of carbohydrate to 33-40% of the required calories and the remaining 60% to be gained from proteins (20%) and fats (40%) [4].
The complex form of carbohydrates is preferable over simple ones as they are absorbed slower without producing significant hyperglycemia.Complex carbohydrates also decrease insulin resistance [6].
If the routine three meals daily failed to achieve the target blood sugar, each meal should be divided in 2:1 or 1:1 ratio to eat 4-6 meals per day [14].
The ADA recommended "MyPlate" as a healthy guide for each meal which consists of 25% protein, 25% starch, and 50% non-starchy foods as vegetables especially steamed ones.Creating MyPlate is a simple and effective method allowing proper control of the blood glucose levels and losing weight (http://www.diabetes.org/food-and-fitness/food/planning-meals/create-your-plate/).Some foods to be avoided include highly processed foods as white bread, fast foods, alcohol, baked products as muffins and cakes, sugary drinks, candy, and high starch foods as white rice and white potatoes.

Exercise
Although there are many randomized studies done to evaluate the effects of physical exercise and lifestyle modifications in adults with diabetes, only few ones evaluated these effects in pregnant women with GDM.These studies proved that exercise improves the blood glucose [8,[15][16][17][18].These beneficial effects may occur as a result of the increase of lean muscle mass with subsequent increase in insulin sensitivity.So a moderate exercise program is highly recommended for women with GDM [11].A moderate intensity aerobic exercise for at least 150 minutes weekly [19] or simple exercise as walking after each meal for 10-15 minutes [20] is recommended.
The Finnish GDM prevention trial (RADIEL)-a multicenter randomized controlled study-evaluated the efficacy of combined dietary and physical activity modifications in prevention of GDM and obesity-related perinatal complications [21].Counseling was achieved through three visits to the study nurse at 13, 23, and 35 weeks of pregnancy.Dietary modification was done according to Nordic Nutrition Recommendations encouraging the intake of vegetables, fruits and berries, high-fiber whole-grain products, low-fat dairy products, vegetable fats high in unsaturated fatty acids, and fish and low-fat meat products with lower intake of sugar-and saturated fatty acid-rich foods.[22].Physical moderate exercise for 150 minutes at least per week is recommended [23].They found that these modifications had no effects on either the incidence of GDM or perinatal complications [24].

Pharmacologic treatment
Pharmacologic treatment is indicated when dietary management and exercise failed to achieve the target glucose levels.
Basically, insulin is the standard treatment for GDM [11].Insulin has the advantage of non-crossing of the placenta.It is given according to the timing of the occurrence of hyperglycemia.If hyperglycemia is present throughout the day both in the fasting and postprandial state, a divided dose of combination of either long or intermediate acting insulin with the short acting one is recommended.The typical total starting dose is 0.7-1 unit/ kg of body weight.If hyperglycemia is detected only at a specific times, focusing the insulin dose at that specific time of hyperglycemia is done, e.g., high fasting blood sugar is treated using a nighttime intermediateacting insulin, while elevated post-breakfast blood sugar is treated by short-acting insulin before breakfast.The maintenance dose is then adjusted according to the monitored blood glucose [4].
The insulin analogs as insulin aspart and lispro are preferred over the regular insulin as a short-acting type.They do not cross the placenta, and their main advantage is their faster onset of action allowing the women to receive their injection at the time of the meal not 10-15 minutes before it as needed in the regular type.This advantage provides better control of the glucose level, and less attacks of hypoglycemia resulted from timing error [25,26].Intermediate-and long-acting insulin include the basic isophane insulin (NPH) and recent insulin glargine and detemir (Table 1) [27][28][29].

Oral antidiabetic medications
Historically oral hypoglycemics should be avoided as early agents cross the placenta, resulting in fetal hyperinsulinemia with subsequent macrosomia and congenital malformations (most commonly in the ear) and severe neonatal hypoglycemia.Now their use in GDM is increasing despite them not approved by the US Food and Drug Administration [31] and the recommendation of ADA that insulin is the first-line therapy for GDM [11] as these products have advantages as ease of tablet intake, ease of storage, and safe needle disposal.
Metformin is a biguanide that decreases intestinal glucose absorption and hepatic gluconeogenesis and increases peripheral glucose uptake.Historically, it was given to women used in pregestational diabetic women and women with polycystic ovary syndrome who suffer from infertility.In the latter group, it was continued until completion of the first trimester, despite the limited evidence of its ability to improve pregnancy outcome [32].Modified from Gabbe and Graves [30].

Table 1.
Describes the onset, peak, and duration of action of the commonly used insulins.
Although metformin can cross the placenta, its long-term metabolic effects on the growing fetus are not known [33].One study showed the absence of any developmental effects till the age of 2 years of life [34].
In a randomized controlled trial, 751 pregnant women having GDM were assigned to treatment with insulin or metformin ± insulin.The perinatal outcome was similar among the two groups [35].
Another smaller trial showed that women assigned to metformin had lower blood glucose, lower maternal weight gain during pregnancy, and lower incidence of neonatal hypoglycemia [36].
In a network meta-analysis that included unpublished trials, there was a difference between insulin and metformin treatments regarding neonatal birth weight, hypoglycemia, or mode of delivery [37].
Therefore, women with GDM are carefully counseled about the use of metformin.They should know that it is not superior to insulin, there are no definitive data about its long-term effects of the growing fetus, and 26-46% of women on metformin will need to add insulin to replace it or to potentiate its effects for better glucose control [35,36].
Metformin starting dose is usually 500 mg once daily at nighttime for 1 week, and then the dose is increased according to the response.The maximum daily dose is 2500-3000 mg daily in two-three divided doses.
Contraindications to metformin include impaired kidney function, and serum creatinine should be evaluated before the start of treatment.
Side effects of metformin occur in 2.5-45.7% of cases [38], and the commonest is GIT upset in the form of abdominal pain and diarrhea.Its use may be associated with higher rate of lactic acidosis, preeclampsia, and neonatal jaundice.So the drug is instructed to be administered with meals and to increase the needed dose gradually.
A systematic review stated that metformin use during pregnancy is safe and effective regarding the short-term pregnancy outcomes.There are no solid guidelines about the duration of metformin use during pregnancy, so it is based on clinical experience on a case-by-case basis [39].
Sulfonylurea used in GDM includes glyburide, tolbutamide, glibenclamide, and gliclazide.Chlorpropamide crosses, while glibenclamide does not cross the placenta.
Glyburide augments insulin secretion by pancreas (through binding adenosine triphosphate potassium channel receptors of the beta cells) and extrapancreatic tissues.It also increases insulin sensitivity of peripheral tissues.It should not be used as a first-line treatment as most studies showed inferior results when compared to insulin or metformin [31].
The dose of glyburide is 2.5-20 mg per day in divided doses.The maximum dose is 30 mg daily [40].Even with these high doses, 4-16% of patients will need the addition of insulin for adequate glycemic control [41][42][43][44].
Contraindications include allergy to sulfa, and side effects include mild infrequent GIT side effects as nausea, vomiting, and diarrhea.
Other sulfonylurea include Thiazolidinedione as Pioglitazone & Rosiglitazone which decrease insulin resistance by reducing RESISTIN hormone released from adipose tissue.Their use during pregnancy cannot be recommended as no enough reports to support their use.A Cochrane meta-analysis evaluated 7381 women with GDM and reported similar pregnancy outcomes when insulin therapy is compared with oral antidiabetic agents (metformin, glyburide, both, and acarbose) [53].However these oral antidiabetic agents have different safety and efficacy, so pooling all of them together against insulin weakens that meta-analysis.
To sum up, the current available data show the absence of short-term hazards, but the long-term effects are still unknown.So, the women should be counseled about the unknown proven safety of the oral antidiabetic agents and the high rate of need for adding insulin before describing it.
ACOG considers insulin as the first-line treatment for GDM and describes oral agents (mainly metformin and rarely glyburide) as an alternative in women who decline insulin use (for financial issues or non-availability of safe administration) after proper consultation.

Other medications used in GDM
As there are many evidences that link oxidative stress and development of complications of diabetes with pregnancy, the use of antioxidants was suggested to improve pregnancy outcome [54].Oxygen free radicals released during aerobic metabolism cause cellular damage [55,56].Many authors reported the participation of reactive oxygen species in diabetes associated with pregnancy [57,58].
An interesting randomized controlled trial was conducted that involved 200 women with GDM who were assigned to receive antioxidant (1 gram L-ascorbic acid daily) or placebo.Maged and colleagues found that antioxidants significantly decreased the required insulin dose to control blood sugar and oxidative markers (glutathione, malondialdehyde, superoxide dismutase).In placental tissue homogenate, maternal blood and neonatal blood were significantly different between the two groups.In the antioxidant group, the neonatal blood sugar was more stable within 2 h of delivery, and the neonatal ICU admission was lower than other women.They concluded that the use of antioxidant administration during pregnancy in women with GDM reverses the oxidative stresses resulting in the improvement of neonatal outcome [59].

Glucose monitoring
Monitoring of glucose control is through blood testing urine analysis for glucose and ketone bodies and glycosylated hemoglobin.
The optimal frequency of blood glucose testing in women with GDM is not known.However, four evaluations daily seem to be satisfactory (fasting and after each meal) [4].
Fasting blood sugar is predictive of neonatal fat mass and subsequent development of childhood obesity and diabetes [60], and 1-h postprandial level was predictive of better blood sugar control and subsequent development of LGA and cesarean delivery [61], so both should be measured.The postprandial measurement can be after 1 or 2 h as the peak glucose level occurs almost 90 min after meals [62].Measurement neither at 1 h nor at 2 h is superior to the other [63][64][65].
After stabilization of the blood sugar, individualization of the frequency of glucose measurement according to the gestational age, adherence of the patient to treatment and the needs of further adjustment is recommended.However the minimum is two measurements per day [4].
Women under self-monitoring of blood glucose daily had significantly lower incidence of fetal macrosomia and less weight gain than those under intermittent measurement of fasting glucose during semi-weekly antenatal visits [66].
de Veciana and colleagues randomly assigned 66 women with GDM for preprandial or 1-h postprandial measurement of blood sugar.They found that postprandial group had better blood glucose control with less macrosomia, cesarean delivery for cephalopelvic disproportion, and neonatal hypoglycemia [61].
A review included 10 trials of 538 women (468 and 70 women with type 1 and type 2 diabetes).Different glucose monitoring methods were compared without clear advantage of one method over the others.Two trials (43 women) comparing self-monitoring versus standard care proved no difference for cesarean section or glycemic control.One study (100 women) compared self-monitoring versus hospitalization and found no clear difference for hypertensive disorders, cesarean section, or preterm birth.Another study (61 women) which compared preprandial versus postprandial glucose monitoring proved no clear difference regarding cesarean section, macrosomia, or glycemic control.Three studies (84 women) which compared automated telemedicine monitoring versus conventional system found no clear difference for cesarean section and mortality or morbidity.CGM was compared to intermittent monitoring in two studies (225 women), and there was no difference for preeclampsia and cesarean section and large for gestational age.One trial (25 women) compared constant CGM versus intermittent CGM and found no clear difference between groups for cesarean section, glycemic control, or preterm birth [67].

Glycosylated hemoglobin
Hemoglobin (Hb) A forms about 90% of hemoglobin in adults, and its glycosylation occurs due to irreversible nonenzymatic binding of glucose to N-terminal of β chain.Hb A 1 is divided into Hb A 1 a1 , Hb A 1 a2 , Hb A 1 b , and Hb A 1 C (the most important).The mean plasma glucose over the erythrocyte life span is correlated with the degree of glycosylation.Its advantages include that it is a single, nonfluctuating blood test that reflects the glucose levels over the last 4-8 weeks.So, HbA1c is an attractive test that can be added to routine investigations done in the first antenatal evaluation as it serves as a diagnostic tool for women with undiagnosed diabetes or at risk of its development [68].If measured during the first trimester, it gives an idea about blood glucose control in the periconceptional period and during organogenesis.Its main disadvantage is its affection by red blood cell turnover [6] which results in the absence of clear recommendations for its use to diagnose GDM [69][70][71].HbA1C increases also in cases of non-hemolytic anemias and chronic renal failure [72].Women with A1c of 10-12% have up to a 25% risk of major malformations.

Fetal assessment
Like women with pregestational diabetes, women with GDM should follow antenatal fetal assessment especially those with poor glycemic control and women under medical treatment with insulin or oral antidiabetic agents [73].It should start at 32 weeks of gestational age and earlier in women with GDM associated with other factors that may adversely affect fetal outcome as hypertensive disorders [74].
There is no consensus about antepartum fetal monitoring in properly controlled women without medical treatment, and if done it usually starts to alter at 32 weeks.The specific test used and its frequency are dependent on the regional practice, but Treatment of Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.86988amniotic fluid measurement is probably included as polyhydramnios is commonly associated with fetal hyperglycemia [4].
At Parkland Hospital, women with GDM are routinely asked to count daily fetal kick especially during the third trimester, and women on insulin treatment are offered for hospital admission and CTG monitoring three times weekly [74].

Obstetrical management
Timing and management of delivery of women with GDM are dependent on glycemic control, fetal condition, and associated complications.Women with proper glycemic control without associated medical problems are followed up till term [75,76].
A comparison was done between women with GDM who were subjected to labor induction at 38 weeks and those who were followed up till 41 weeks of gestation, which revealed similar CS rate and all other outcomes except the higher occurrence of neonatal hyperbilirubinemia in one study [77], lower incidence of LGA in another study [78], and lower incidence of shoulder dystocia in a third one [79] in the induction group.A more recent study found a lower rate of CS in the induction group [80].So women with GDM using medications with proper control of blood sugar delivered better during the 39 weeks of gestation [4].
In women with poor control of their blood sugar, timing of delivery is determined by balancing the risk of prematurity and the ongoing risk of intrauterine fetal death.In general earlier delivery in women with good glycemic control is recommended [75,76], but the clear guides for glycemic control and timing of delivery are absent [81].In general delivery between the start of 37 weeks and the completion of 38 weeks appears appropriate, while delivery at 34 weeks till the completed 36 weeks should be attempted only in women with abnormal fetal wellbeing assessment and those with failed hospital control of blood sugar [4].
Ultrasound assessment of fetal size should be done in all women with GDM.However only 22% of fetuses diagnosed as LGA by ultrasound had macrosomia after birth [82].To prevent one case of permanent brachial plexus injury, 588 and 962 CS should be performed for ultrasonographic estimated fetal weight of 4500 and 4000 gm, respectively [83,84].So women with GDM and macrosomic fetus should be counseled about the elective CS risks and benefits [85].

Postpartum evaluation
Women with GDM should be evaluated postpartum as 15-70% will develop diabetes later in life [86][87][88][89][90].These women were estimated to have sevenfold increased risk of developing type 2 DM when compared to controls [91].So, screening after 4-12 weeks of delivery is recommended to identify those with diabetes, impaired fasting glucose levels, or impaired glucose tolerance [11] (Figure 1).
ACOG practice bulletin No. 190: Gestational diabetes mellitus [4].The Fifth International Workshop-Conference on Gestational Diabetes recommended that women with GDM undergo evaluation with a 75-g oral glucose tolerance test at 6-12 weeks postpartum [92].These recommendations are shown in Table 2.
Women with GDM are at an increased risk for cardiovascular complications associated with dyslipidemia, hypertension, and abdominal obesity-the metabolic syndrome [74].
Kessous and colleagues found that women with GDM were 2.6 times more likely to be hospitalized for cardiovascular morbidity [93].
Shah and coworkers also reported excessive cardiovascular disease by 10 years in women with GDM [94].

Recurrent gestational diabetes
The risk of recurrence of GDM is estimated to be 40% in primiparous women [95].Women with higher body mass index are more likely to have impaired glucose tolerance in subsequent pregnancies.Therefore, lifestyle modifications, including weight control and exercise between pregnancies, may prevent the recurrence of GDM [96].Overweight and obese women in their first pregnancy will lower the risk of GDM, if they lose 2 or more units of their body mass index [97].The risk of GDM in second pregnancy was 4.2% in women without GDM in their first pregnancy against 41.3 percent in those with a history of gestational diabetes in their first pregnancy [98].

Contraception
Women with recent GDM can use low-dose hormonal contraceptives safely as the rate of developing of diabetes is similar in oral contraceptive users and nonusers

Table 2.
Fifth international workshop-conference: Metabolic assessments recommended after pregnancy with gestational diabetes.
Treatment of Gestational Diabetes DOI: http://dx.doi.org/10.5772/intechopen.86988 of any hormonal contraception [99].Care should be taken in women at risk of cardiovascular diseases as obese, hypertensive, and dyslipidemic women with direction of the contraceptive choice toward a method without potential cardiovascular consequences as intrauterine device.
Studies were reviewed and evaluated for quality according to the method outlined by the US Preventive Services Task Force: I Evidence obtained from at least one properly designed randomized controlled trial.
II-1 Evidence obtained from well-designed controlled trials without randomization.
II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
II-3 Evidence obtained from multiple time series with or without the intervention.Dramatic results in uncontrolled experiments also could be regarded as this type of evidence.
III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.