Study of Gestational Diabetes Mellitus: A Brief Review

 

Sachin B. Somwanshi¹, Punam D. Bairagi¹, Kiran B. Kotade²

¹Department of Pharmaceutics, P.R.E.S.’s, College of Pharmacy (For Women), Chincholi, Sinnar, Nashik, Maharashtra, India-422102

²Department of Pharmacology, P.R.E.S.’s, College of Pharmacy (For Women), Chincholi, Sinnar, Nashik, Maharashtra, India-422102.

 

ABSTRACT:

Gestational diabetes mellitus (GDM) is highly prevalent metabolic disorder varied in degrees of intensity starting with pregnancy or noticed during pregnancy. It is associated with maternal and neonatal adverse outcomes. The prevalence of GDM is increasing worldwide and parallel to the increment in the prevalence of obesity and type 2 diabetes mellitus. It is essential to diagnose and treat GDM early, in order to reduce or avoid complications for mother and fetus. There is a lack of uniformity in screening and diagnosing GDM globally. This review covers the latest update in the diagnosis and management of GDM. Treatment must be individualized for best results, including a medical nutrition therapy supplementary diet and exercise. If these measures fail to control the blood glucose levels, the use of pharmacologic interventions should be initiated includes mainly Insulin and their analogs. Other oral antihyperglycemic agents such as Metformin and Glyburide are also discussed, in face of new facts regarding their safety and efficacy during pregnancy.

 

 

 

INTRODUCTION:

Pregnancy is associated with insulin resistance (IR) and hyperinsulinemia that may predispose some women to develop diabetes.¹ Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance in varied degrees of intensity starting with pregnancy or noticed during pregnancy.² Five decades ago, GDM was used to detect pregnant women who were at a higher risk of developing type 2 diabetes mellitus (DM2) after childbirth. Currently, GDM is used to predict morbidity in index pregnancy.

 

Women with diabetes mellitus who become pregnant have more harmful complications (due to the severe hyperglycemia since early pregnancy) compared to pregnant women developing mild hyperglycemia in late pregnancy. The former have diabetes in pregnancy while the latter are diagnosed with GDM. Thus, GDM implies a milder form of hyperglycemia seen generally in late pregnancy, which usually, but not always, reverts to normal after delivery.³

 

The gestational diabetes mellitus is a common metabolic problem, measured an important concern. For this reason, the diagnostics is exceedingly important. The diagnostic measures for GDM were first described 40 years ago; however, there is no single screening method complying with the international standards. Due to a great demand for uniformity in the diagnosis and classification of GDM, the challenge to accept such strategy is well-known and discussed for years. The tests that have been used until recently have mostly focused on the risk of developing diabetes in future life after pregnancy and not on perinatal outcomes of GDM.⁴

 

Prevalence:

The prevalence of diabetes mellitus is increasing worldwide and parallel to the increment in the prevalence of obesity and type 2 diabetes mellitus.⁵ The prevalence rates for GDM are higher for African, Hispanic, Indian, and Asian women than for Caucasian women.¹ The International Diabetes Federation estimated that worldwide 16% of live births in 2013 were complicated by hyperglycemia during pregnancy and the increasing prevalence due to the increase in risk factors like obesity and physical inactivity.⁶ Depending on the population studied and the employed diagnostic test, prevalence of GDM may range from 2.4 to 21 per cent of all pregnancies. In India, due to wide dissimilarities in living conditions, socioeconomic levels and nutritional habits it is difficult to predict any uniform prevalence levels.⁷

 

Classifications of Diabetes in Pregnancy:

World Health Organization (WHO) and National Diabetes Data Group (NDDG) of National Institutes of Health (NIH) have recognized a classification based on the etiology. WHO classification differs only by recognizing impaired glucose tolerance (IGT) before pregnancy.⁸

 

Classification of maternal diabetes in pregnancy:

1.      Pregestational diabetes: Pre-existing Type 1 or type 2

2.      Gestational diabetes: Diagnosis is made post-gestational; normal glucose tolerance

3.      Any type of diabetes occur first in pregnancy⁸

 

A uniform classification is still needed for both epidemiological and clinical purpose. Generally there are 2 different methods. The first is the White classification (Table 1) who applied by most European Centers, and the second is the American Diabetes Association (ADA) classification (Table 2).⁹

 

Table 1: White Classification

Class A	Abnormal glucose tolerance test at any age or of any duration treated only by diet therapy
Class B	Onset at age 20 years or older and duration of less than 10 years
Class C	Onset at age 10 to 19 years or duration of 10 to 19 years
Class D	Onset before 10 years of age, duration over 20 years, benign retinopathy, or hypertension (not preeclampsia
Class R	Proliferative retinopathy or vitreous hemorrhage
Class F	Renal nephropathy with over 500 mg/d proteinuria
Class RF	Criteria for both classes R and F
Class G	Many pregnancy failures
Class H	Evidence of arteriosclerotic heart disease
Class T	Prior renal transplant

Table 2: American Diabetes Association Classification

3 Forms of Glucose Intolerance
Type I diabetes	Immunologic destruction of the pancreas
Type II diabetes	Exhaustion or resistance of the pancreatic cells
Gestational	A glucose intolerance that had not previously been present prior to pregnancy

 

Pathophysiology:

During pregnancy, a number of maternal metabolic changes occur early and continue throughout pregnancy which helps to optimize the transfer of nutrients to the fetus. During normal pregnancy, there is a decrease in insulin sensibility which is physiological, progressive and reverse. The past; In the last century insulin resistance and the decrease in insulin sensitivity during pregnancy is mainly attributed to the increase in the levels of pregnancy-associated hormones as estrogen, progesterone, cortisol, and placental lactogen in the maternal circulation. Normally the insulin resistance of the whole body is increased to about three times that seen in the non-pregnant state.

 

The increased resistance is caused by post-insulin receptor events and is probably brought about by the cellular effects of the increased levels of one or all of the above hormones. As pregnancy progresses and the placenta grow larger, hormone production also increases and so does the level of insulin resistance. This process usually starts between 20 and 24 weeks of pregnancy. At birth, when the placenta is delivered, the hormone production stops and so does the condition, strongly suggesting that these hormones cause GDM.¹⁰

 

Risk Factors:

Many risk factors for GDM have been identified. Screening of GDM is important because it aims to identify women who are at high risks to develop the disease, in order to reduce or avoid risks to maternal and fetal health. Current selective screening guidelines have high sensitivity but low specificity and offer little over universal screening. The considerations that determine the greatest risk to disease are includes maternal age, increasing body mass index (BMI), ethnicity, family history of type 2 diabetes and previous history of GDM, previous poor obstetric history. Additional risk factors of a macroscopic baby in a previous pregnancy outcome, a women’s own low birth weight, glycosuria, polyhydramnios or a large for gestational age fetus in the current pregnancy.¹¹

 

In addition to this, statistics show a double risk of GDM in smokers.¹² Polycystic Ovarian Syndrome (PCOS) is also a risk factor however the debate over PCOS may predispose to GDM continues.¹³

 

Figure 1: Risk factors for gestational diabetes mellitus

 

Signs and Symptoms:

Women with gestational diabetes usually have no symptoms or mild, non-life-threatening symptoms, according to the NIH. These symptoms are mostly related to abnormal blood sugar levels, and can include fatigue, excessive thirst and increased urination.¹⁴ The symptoms of GDM are as follows;

 

Figure 2: Symptoms of GDM

Diagnosis:

Tests for gestational diabetes are usually done around 24 to 28 weeks of pregnancy, according to the NIH. Some women may be tested earlier in pregnancy if they are at increased risk for gestational diabetes. Women first undergo a glucose screening test, in which they drink a sugar solution, and their blood sugar level is tested one hour later. If a woman's blood sugar level is higher than normal, they will need to undergo a second test, called a glucose tolerance test, according to the NIH. To prepare for the glucose tolerance test, the mother will need to fast for 8 to 14 hours before her doctor's visit. Her blood is taken before the test, and again in 30- to 60-minute intervals over two to three hours after she drinks a high-glucose solution in order to measure how blood glucose and insulin level changes over time. Most women who take the glucose tolerance test (two out of three) do not have gestational diabetes, the NIH says.

 

If a woman is diagnosed with gestational diabetes, glucose tolerance tests are usually conducted once more at around six to 12 weeks after the woman gives births, and then once every one to three years in order to identify any lingering glucose intolerance.¹⁴ Faced with the various diagnostic parameters used worldwide and the lack of standardization, in 2014, ADA (American Diabetes Association) recommends new criteria for diagnosis. Pregnant women in early pregnancy who do not meet the diagnostic criteria for GDM should be retested between 24th and 28th gestational weeks. A single positive test is enough for the diagnosis, according to the information shown in Table 3.¹⁵

 

Table 3: Diagnostic criteria for overt diabetes and gestational diabetes using a 2-hour 75-g OGTT at 24 to 28 weeks gestational

Diagnosis	Fasting Plasma Glucose, mg/dL	1-h Value, mg/dL	2-h Value, mg/dL
Overt diabetes (type 1, type 2, or other)	≥126 mg/dL	Not applicable.	≥200 mg/dL
Gestational diabetes	≥92 mg/dL	≥180 mg/dL	≥153 mg/dL

 

Complications:

There are both fetal and maternal complications associated with GDM.

 

Fetal Complications:

These include macrosomia, neonatal hypoglycemia, perinatal mortality, congenital malformation, hyperbilirubinemia, polycythemia, hypocalcaemia and respiratory distress syndrome. Neonatal hypoglycemia can occur within a few hours of delivery. This results from maternal hyperglycemia causing fetal hyperinsulinemia. Long term complications to the offspring include an increased risk of glucose intolerance, and obesity.

Maternal Complications:

These include hypertension, preeclampsia and an increased risk of cesarean delivery. More important is women with GDM have an increased risk of developing diabetes after pregnancy when compared with the general population, with a conversion rate of up to 3% per year.¹⁶

 

Management of Gestational Diabetes Mellitus:

GDM is characterized by increased risk of macrosomia and birth complications and an increased risk of maternal type 2 diabetes after pregnancy. The risks increase with progressive hyperglycemia. The aim of the management is to maintain normal blood glucose levels through pregnancy, and avoid periods of hypoglycemia and hyperglycemia. The main therapeutic goal throughout pregnancy is to avoid the adverse events caused by hyperglycemia. GDM is managed initially with Medical Nutrition Therapy (MNT) for 2 weeks.

 

 

Figure 3: Gestational diabetes mellitus management model

 

Medical Nutrition Therapy:

Principles of MNT:

All pregnant women with GDM should get Medical nutrition therapy (MNT) as soon as diagnosis is made. MNT for GDM primarily involves a carbohydrate controlled balanced meal plan which promotes;

ü  Optimal nutrition for maternal and fetal health

ü  Adequate energy for appropriate gestational weight gain,

ü  Achievement and maintenance of normoglycemia

 

Nutrition assessment in GDM should be individualized to allow an accurate appraisal of the woman’s nutritional status. This assessment includes defining her Body Mass Index (BMI) or percentage of desirable pre-pregnancy body weight and optimal pattern of weight gain during pregnancy¹⁷. The expected weight gain during pregnancy is 300–400 g per week and total weight gain is 10–12 kg by term.¹⁸

 

Pharmacologic Interventions:

Insulin Therapy:

Insulin therapy is the accepted medical management of pregnant women with GDM not controlled on MNT in 2 weeks. It is the preferred agent because of the lack of long-term safety data for noninsulin agents¹⁹.

 

1. Preferable to start with Premix insulin 30/70 of any brand*

Starting dose: 4 units before breakfast

↓

Every 4th day increase 2 units till 10 units

↓

If FPG remains > 90 mg/dL advise → 6 units before breakfast and 4 units before dinner

↓

Review with blood sugar test → Adjust dose further

 

Total insulin dose per day can be divided as two-thirds in the morning and one-third in the evening.

[*Initially if post-breakfast plasma glucose is high → Start Premix 50/50]

 

2. If GDM is diagnosed in the third trimester; MNT is advised for a week. Insulin is initiated if MNT fails.

 

3. If 2-hour PG > 200 mg/dL at diagnosis, a starting dose of 8 units of Premixed insulin could be administered straightaway before breakfast and the dose has to be titrated on follow-up. Along with insulin therapy, MNT is also advised.¹⁹

 

Site of Insulin Injection: ¹⁷

ü  Front/Lateral aspect of the thigh or over abdomen

ü  Insulin injection is to be given subcutaneously only.

 

 

Figure 4: Insulin Injection Sites

 

Insulin Analogs:

If postprandial glucose is still not under control—consider using rapid-acting insulin analogs. Insulin analogs are the remodel insulin molecules with the purpose of changing its pharmacokinetics properties which influences the association of molecules as well as duration of insulin-receptor binding leads to an increased mitogenic action of insulin analogs. The main analogs are Lispro insulin, Insulin as part, detemir and glulisine having improved pharmacokinetic and Pharmacodynamics properties.²⁰ Insulin glargine is not approved in pregnancy, but the existing studies did not show any contraindications.²¹

 

Oral Antihyperglycemic Therapy:

1.      Metformin:

Metformin may be associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin; however, metformin may slightly increase the risk of prematurity. Furthermore, nearly half of patients with GDM who were initially treated with metformin in a randomized trial needed insulin in order to achieve acceptable glucose control. Umbilical cord blood levels of metformin are higher than simultaneous maternal levels. Patients treated with oral agents should be informed that they cross the placenta, and although no adverse effects on the fetus have been demonstrated.²²

 

2.      Glyburide:

Glyburide is an antidiabetic sulfonylurea derivative (micronized form of glibenclamide) which acts by binding to the pancreatic beta cell receptors, blocking the potassium channel and opening calcium channels, stimulating insulin release. As it reduces hepatic glucose production, it contributes to fasting hyperglycemia.² Concentrations of glyburide in umbilical cord plasma are approximately 70% of maternal levels. Glyburide may be associated with a higher rate of neonatal hypoglycemia and macrosomia than insulin or metformin.²²

 

 

Table 3: Oral Antihyperglycemic Therapy

Medication	Crosses Placenta	Classification	Notes
Metformin	Yes	Category B	1. Meformin and glyburide may be insufficient to maintain normoglycemia 2. Long-term safety of these agents during pregnancy is unknown
Glyburide	Minimal Transfer	Some formulations category B (Micronase), others category C (Diaβeta)

 

3.      Other Drugs:

Acarbose, thiazolidinediones or incretin are used as a mimetics and enhancers in pregnancy by considering their data about the safety or efficacy. Currently these drugs are not recommended and their use in pregnancy should be considered experimental.²³

 

Dietary supplementation with myo-inositol:

Myo-inositol is emerging potential intervention for treating gestational diabetes which is an isomer of inositol and occurs endogenously and is found in natural dietary sources such as fruits, vegetables, nuts and cereals. Brown et al reported that myo-inositol was associated with a reduced change in maternal BMI and fasting blood sugar concentration compared with placebo. Uncertainty of the effectiveness of myo-inositol as a treatment for GDM for key maternal and infant outcomes remains and further high- quality trials with appropriate sample sizes are required to further investigate the role of myo-inositol as a treatment or co-treatment for women with gestational diabetes.²⁴

 

Exercise guidelines for gestational diabetes mellitus:

The management of GDM aims to mediate the effects of hyperglycaemia by controlling blood glucose levels. Along with pharmacology and dietary interventions, exercise has a powerful potential to assist with blood glucose control. Due to the uncertainty of risks and benefits of exercise during pregnancy, women tend to avoid exercise. However, under adequate supervision exercise is both safe and beneficial in the treatment of GDM. Therefore it is vital that exercise is incorporated into the continuum of care for women with GDM. It is recommended that women with GDM should do both aerobic and resistance exercise at a moderate intensity, a minimum of three times a week for 30-60 min each time.²⁵ Light to moderate physical activity during a normal pregnancy provides various benefits for the mother and her fetus such as walking and cardiovascular training with weight-bearing, limited to the upper body to avoid mechanical stress on the abdominal region. For mothers, it helps reduce and prevent lower back pain, decreases fluid retention, reduces cardiovascular stress, increases oxygenation capacity and decreases blood pressure. Fetal benefits include decreased fat mass, reduced risk of being a LGA fetus, improved stress tolerance, and advanced neurobehavioral maturation. Recent observational studies have found physical activity during normal pregnancy decreased insulin resistance and therefore, might help to decrease the risk of GDM.²⁶

 

CONCLUSION:

Gestational diabetes mellitus is a disease with serious consequences to the mother and the fetus, showing some irreversible complications on metabolism. The prevalence of GDM is raising worldwide parallel to the increment in the prevalence of obesity and DM2. An appropriate screening, diagnosis and management is important to improve perinatal and maternal outcomes, which decreases the incidence of DM2 in the future. The treatment of gestational diabetes mellitus must start as soon as the diagnosis is established. The treatment with pharmacologic interventions has an important role on lowering the complications related to GDM. Insulin, Metformin and Glyburide are good alternatives. Also various medical nutrition therapy and exercises can reduce the re-existence of GDM in the next pregnancy.

 

ACKNOWLEDGEMENT:

We would like to thank P.R.E.S.’s, College of Pharmacy, Chincholi, Nashik for giving a platform to do such review and publish this manuscript.

 

CONFLICT OF INTERESTS:

Declared none

 

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Received on 17.04.2017       Accepted on 28.05.2017     

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