Gestational diabetes mellitus

INTRODUCTION
DEFINITION
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.It does not exclude the possibility that unrecognized glucose intolerance may begin concomitantly with the pregnancy1
Cause for Gestational Diabetes
Pregnancy is mainly a glucose intolerant condition. As pregnancy advances, the sensitivity to insulin decreases and this may predispose to the development of gestational diabetes mellitus (GDM), mainly in fat women with preexisting insulin resistance. GDM develops if there is no sufficient insulin secretion to compensate for the increased insulin resistance.2

EPIDEMIOLOGY
Prevalence of gestational diabetes mellitus seems to vary worldwide. It may range from 2.4 to 21 per cent of all pregnancies, depending on the population studied and the diagnostic tests employed. 3,6.Because of the wide differences in living conditions, socio-economic levels and dietary habits, it has been difficult to predict any prevalence in India. However among Kashmiri women a 3.8% of GDM prevalence was observed.5
Surveys performed in various places in India during the year 2002-2003, an overall prevalence of 16.55%GDM was found. In a study carried out in Tamil Nadu, in urban areas, GDM was detected in 17.8 per cent women whereas 13.8 per cent women in semi-urban while in rural areas a prevalence of 9.9 per cent was observed.6.

Risk factors for GDM
There are several health factors that increase the risk of developing GDM, for example, older age, previous history of GDM, body mass index (BMI) >30 kg/m2, family history of diabetes mellitus, previous history of macrosomic baby weighing ‘4.5 kg, along with ethnicity of high prevalence, particularly in South Asian, black Caribbean, and Middle Eastern.7
The main risk factors for GDM include higher BMI, greater maternal age, member of an ethinic group at development of type 2 diabetes mellitus (i.e.,African, south or East Asian,Hispanic, Native American or pacific inlands ancestry),past history of GDM, history of unexplained still birth, macrosomia in previous pregnancy, polyhydramnios, polycystic ovary syndrome, type 2 diabetes mellitus in a first degree relative and metabolic syndrome.8

Complications,Maternal and Fetal Outcomes
The pregnancy outcome among mothers with GDM is unsatisfactory when compared to non-diabetic women . Patients with border-line GDM has been associated with high rates of perinatal complications. Women with GDM have more number of caesarean sections and induced deliveries.9

About 10-30% of women with GDM develop preeclampsia (PE), as well as another major pregnancy disorder. PE exposes the patient to perinatal complications such as prematurity, perinatal death, and intrauterine retardation of growth. 10
In GDM, concurrent pregnancy-induced hypertension further increases the adverse outcomes 11.
For the mother, GDM is an indicator of increased risk of developing overt diabetes.
Almost 10% of patients with prior GDM were diagnosed with T2D soon after delivery and, within a ten-year follow-up, the risk of developing T2D was found to be 40% [6]. There is a is high cumulative incidence of T2D within the first 5 years following pregnancy and then it declines in ten years postpartum. 9
After delivery, women with GDM often have a greater risk for metabolic syndrome, and shortly after delivery these women expresses early signs of vascular diseases such as increased intima-media thickness of carotid arteries and disturbed endothelial function.12

The offsprings of GDM mothers are at increased risk of fetal,neonatal and long term morbidities. They are at higher risks of developing several anomalities, stillbirths and macrosomia. Fetal macrosomia defined as a birthweight >4000 or 4500 g, that is large for gestational age (LGA).Macrosomia is one of the most common morbidity, occurring in 15%-45% of infants, leading to shoulder dystocia , need for caesarean sections, trauma during delivery and perinatal morbidity, such as birth asphyxia . Respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, hypocalcemia, hypertrophic cardiomyopathy and polycythemia are the complications generally encountered in the immediate postnatal period. Offsprings are also at greater threat of developing diabetes, metabolic syndrome and obesity in childhood and as well as in adult life. The depth of fetal and neonatal risks were linked to the severity of maternal hyperglycemia13
Several studies have demonstrated that the chance of adverse pregnancy outcomes increases continuously with elevated glucose levels and can be reduced with effective treatment. However, interventions to modify lifestyle have shown to improve perinatal outcomes, and if hyperglycemia continues, treatments with insulin, are often recommended. 14
While effective, insulin therapy has several disadvantages for pregnant women. Therefore, a safe and effective oral agent would offer advantages over insulin. Metformin, as the first choice of medication for type 2 diabetes mellitus (T2DM) in non pregnant patients is an oral agent candidate for GDM14
DIAGONOSTIC CRITERIA
The oral glucose tolerance test (OGTT) are most commonly used to diagnose Gestational diabetes mellitus. The usual recommendation for screening is between 24 weeks and 28 weeks of gestation, on following this the chance of detecting unrecog”nized type 2 diabetes before pregnancy (pre-GDM) is likely to be missed. So all the women who are pregnant should be monitored for the GDM from early weeks of gestation to till delivery.15
.

ADA recommended all obstetric patients to be classified into low, average and high risk. Patients who satisfied all of the following criteria would be at low risk and does not require GDM screening.This include patients less than 25 years old, ethnic group among which GDM prevalence is low, absence of diabetes in first-degree relatives, normal pre-pregnancy weight, no previous history of abnormal glucose metabolism as well as no poor obstetric outcome. Patient with severe obesity, strong family history of type 2 diabetes, previous history of GDM, impaired glucose metabolism, or glucosuria would be a threat and so testing should be carried out as fast as possible in this group. The remaining patients were at an average risk and so should be tested for GDM at 24’28 weeks. High risk patients who were not diagnosed earlier should take a second test at the same time period. The National Institute for Health and Clinical Excellence (NICE) guideline, in the year 2008, recommended that all women at their first antenatal visit should be checked for any risk factors 16.
Women with body mass index (BMI) > 30kg/m2, previous macrosomic baby weighing 4.5 kg or more, history of GDM, first-degree relatives with history of diabetes or family origin with a high frequency of diabetes should be offered a diagnostic test using 75g, 2-hour oral glucose tolerance test (OGTT) at 24-28 weeks. Females with history of GDM should receive OGTT at 16’18 weeks and a further OGTT at 28 weeks if the results were normal.17
However, selective screening of risk factors might miss at least 30% of the women with GDM, exposing them to develop adverse outcome, making this approach not feasible. Randomized trial carried out recently has reported the benefits of treating GDM and the subsequent reduction of healthcare cost with worldwide screening.There were two strategies to screen the study population. The one-step approach addressed to identifying GDM with diagnostic OGTT, without prior plasma or serum glucose screening. The two-step approach intended to carry out a diagnostic OGTT only if the first screening test was positive. Random glucose, glycated protein, fasting glucose fasting capillary glucose, 50g 1-hour glucose challenge test (GCT) had all been proposed as the tool for screening recommended before a diagnostic OGTT in ‘two-step’ approach18

Table given below summarizes IADPSG, ADA,ACOG,RANZCOG and WHO criteria for the diagnosis of GDM
Carpenter and Coustan/ ADA (2004)* ACOG (2011)* WHO/NICE (2008)+ RANZCOG (2011)+ IASPSG/ ADA (2012)+
75g OGTT 100g OGTT 100g OGTT 75g OGTT 75g OGTT 75g OGTT
Fasting 5.3mmol/l or
95mg/dl 5.3mmol/l
Or
95mg/dl 5.3mmol/l
Or
95mg/dl 7mmol/l
Or
126 5.5mmol/l
Or
5.1mmol/l
Or
92mg/dl
1-h 10mmol/l or
180mg/dl 10mmol/l
Or
180mg/dl 10mmol/l
Or
180mg/dl 10mmol/l
Or
180mg/dl
2-h 8.6mmol/l or
155mg/dl 8.6mmol/l
Or
155mg/dl 8.6mmol/l
Or
155mg/dl 7.8mmol/l
Or
140 8.0/9.0mmol/l
Or
8.5mmol/l
Or
153mg/dl
3-h 7.8mmol/l
Or
140mg/dl 7.8mmol/l
Or
140mg/dl
*Diagnosis made if two or more glucose value met or exceeded.
+Diagnosis made if one or more glucose value met or exceeded.
PATHOGENESIS
Pregnancy is a diabetogenic condition characterized by insulin resistance with an offsetting increase in ”-cell response and consequently hyperinsulinemia. Insulin resistance usually commences in the second trimester and gradually increases throughout the period of the pregnancy. Insulin sensitivity is declined by as much as 80%. Placenta begins to secrete hormones, such as progesterone, placental lactogen, cortisol, growth hormone and prolactin triggers the insulin-resistant state seen in pregnancy. The insulin resistance often plays a role by ensuring that the fetus has a sufficient supply of glucose by altering the maternal energy metabolisom from carbohydrates to lipids.19
Women with GDM have a greater chance of insulin resistance compared to the insulin resistance seen in normal pregnancies. As a result there is a damage in compensatory increase in secretion of insulin, particularly in its first-phase. This increase in first phase insulin release may be an indicator for ”-cell function. In addition, the women with GDM showed 67% reduction in their ”-cell compensation when compared with normal pregnant control patients.19
Insulin requirements are elevated during normal late pregnancy and changes only slightly between normal and gestational diabetic women. In contrast to healthy women, GDM women shows a consistent reduction in insulin responses to nutrients. The majority of women with GDM appears to have ”-cell dysfunction due to chronic insulin resistance that might have existed before pregnancy. Both obese and lean women with GDM show specific resistance to insulin in triggering glucose excretion and thereby suppressing both glucose production and fatty acid levels . Any defects in the binding of insulin to its receptor in skeletal muscle does not involve in the state of insulin resistance as in GDM women. Many other defects, such as reduced expression of PPAR”, changes in the insulin signaling pathway, and reduced insulin mediated glucose transport have been observed in skeletal muscle or fat cells of women with GDM. However recent studies have also proposed that steps leading to the development of GDM is begun by the fetus itself. Human leukocyte antigen-G (HLA-G) expression, acts to safeguard the fetus from immune attack by cytotoxic T cell response down-regulation to fetal trophoblast antigens. This has also been assumed to protect the pancreatic islet cells . The interaction between HLA-G and nuclear factor-”B (NF-”B) is assumed act centrally in the events leading to GDM development. In GDM women, defects in ”-cell function may be due to autoimmune destruction of ”-cells of pancreas, as in type 1 diabetes. This is attained by circulating immune markers acting against pancreatic islets (anti-islet cell antibodies) or ”-cell antigens (such as glutamic acid decarboxylase, GAD)9
PATHOPHYSIOLOGY OF GESTATIONAL DIABETES MELLITUS
MANAGEMENT OF GESTATIONAL DIABETES
The first line management of women with gestational diabetes mellitus consists of medical nutrition therapy along with exercise for at least 30 min per day. Patient who fail to maintain glycemic control through exercise and diet therapy will receive insulin injections or other antidiabetic medications.20
Diets
For GDM women the normal calorie requirement is 30-35 kcal/kg for normal weight, whereas 25-30 kcal/kg for overweight and 35-40 kcal/kg for underweight subjects. However a calorie restriction to < 1500 cal/d is not advisable. A study by Rizzo et al 21 has shown that an extreme calorie restriction to < 1500 cal/d is linked with greater incidence of ketonemia, leading to mental developmental index scores and average Stanford-Binet scores in the babies. The American Diabetes Association recommends a 30%-33% calorie restriction in obese women with GDM. A minimum intake of 1800 cal/d is acceptable22.
Intake of diets comprising of 50%-60% carbohydrates will often leads to hyperglycemia and excessive weight gain. So, intake of calories from carbohydrate has to be reduced to 33%-40%, with the remaining calories partitioned between protein (20%) and fat (40%)23. Three meals and two to three snacks are advised to distribute intake of glucose and to decrease postprandial glucose fluctuations. Glycemic food index may also be an essential component for sugar control.
Exercise
Up to 39% of women with gestational diabetes mellitus cannot meet glucose targets through diet alone. Physical activity may improve glucose tolerance by improving insulin sensitivity involving muscle glucose uptake and glycogen synthesis ,and therefore physical activity is a logical adjunct to dietary therapy24. The diet and exercise group together decrease the glycated hemoglobin levels an in both fasting and 1-hour plasma glucose levels during a glucose challenge test compared to diet alone25
Insulin
Within 1-2 weeks of diet when the glycemic control is not achieved, pharmacological treatment is recommended26. Short acting insulin is used to control the immediate rise in glucose following the meal and intermediate acting insulin is given for hepatic glucose production in the fasting state. Regular human insulin (RHI) is short acting insulin while neutral protamine hagedorn (NPH) is the intermediate acting insulin in common practice to date27. Short acting insulin starts its action with half an hour to one hour after injection and its effect reaches a peak at 2-4 h. Therefore, at times, the pre-prandial administration of RHI cannot control the elevated postprandial blood glucose. At the same time, delayed peak action and a prolonged duration of action will result in improper hyperinsulinemia before the next meal, resulting in pre-prandial hypoglycemia28.
Rapid acting insulin analogs
This problem can be overcome with newer rapid acting insulin analogs were used instead of short acting insulin. These rapid acting insulin analogs start their action within 15 min, reaches a peak by 31-70 min and acts for 2-4 h. Several studies have revealed the safety of insulin aspart and lispro in pregnancy. United States Food and Drug Administration (FDA) has approved both insulins for use during pregnancy. Several clinical studies have shown fewer episodes of hypoglycemia, strict sugar control and higher reduction in HbA1c levels in pregnancy. 13
Long acting insulin
Commonly used NPH insulin starts its action in 1-2 h, with peak action at 4-8 h and effective up to 12-18 h. The dose of NPH at night has its maximum action in the early morning hours and produces hypoglycemia28.
Other than NPH, long acting insulin analog detemir starts its action in 1-2 h and has a flatter profile with a more even distribution of metabolic effect over 24 h29. Insulin detemir also shows lower rates of hypoglycemia. It has proved by various studies about efficacy and safety of insulin detemir in pregnancy.

Premixed insulin preparations
Premixed insulin preparations are commonly being used. A mixture of short acting and intermediate acting injections are available in different proprtions of 30/70, 25/75, 50/50. Premixed insulin analogs provide better postprandial coverage and less hypoglycemic attacks between meals. Biphasic insulin aspart (BIAsp 30) comprises of rapid acting aspart combined with protamine-crystallized insulin aspart in a 30:70 ratio. It is taken twice daily and provides better sugar control30. It has been found to be harmless during pregnancy.
Insulin pump
Insulin pumps allows flexible insulin administration with a profile that mimics the physiological insulin features of the beta cells of the pancreas. Major benefit of administering insulin by constant subcutaneous insulin infusion include decreased variability in insulin absorption, decreased risk of hypoglycemia (due to the lower total doses of insulin) and improved control of the dawn phenomenon31
Oral hypoglycemic agents for GDM
The traditional management of women with GDM is to provide insulin therapy if diet therapy does not control the sugar levels. However, insulin therapy has its own drawbacks. Now there is emerging proof for the importance of oral medications in these women. ACOG and National Institute for Health and Care Excellence (NICE) guidelines recommends that oral and insulin medications are equivalent in efficacy and either can be an appropriate first-line therapy16

Metformin
Su et al32 conducted a systematic review of six randomized clinical trials involving 1420 subjects. They observed that the use of metformin in women with gestational diabetes has no no increase in adverse maternal and neonatal outcomes compared to insulin. I, metformin usage in pregnancy is associated with less weight gain and neonatal hypoglycemia.
Niromanesh et al 33 conducted a randomized control trial, which showed that the birth weight of the neonate was lower in the metformin group than that of insulin group, though not statistically significant. Maternal weight gain was greatly reduced in the metformin group.
A retrospective study done by Marques et al14showed that there was no statistical changes between insulin and metformin groups with respect to the rates of abortion, preeclampsia, macrosomia, prematurity, less for gestational age or greater for gestational age newborns, perinatal deaths, cesarean deliveries, neonatal intensive care unit admissions and malformations at birth or neonatal injuries.
No significant difference was found in postprandial glucose control between women on insulin and those on oral hypoglycemic agents. This finding is reflected in similar frequencies of fetal macrosomia and mean birth weight in women receiving insulin or oral hypoglycemic agents as first-line treatment34
The MIG trial by Rowan et al35 showed that women receiving metformin had less weight gain between the time of inclusion and 36 wk of gestation than those receiving insulin. Similarly, there was a greater weight loss between the enrollment time and the postpartum visit in women receiving metformin compared to insulin. There were significantly less attacks of neonatal hypoglycemia events in infants of women taking metformin. The MIG trial concluded that metformin had same perinatal complications compared to insulin. Due to the convenience, women preferred metformin to insulin treatment.
The exposed children were observed to 2 years in the MiG-TOFU trial revealed that metformin-exposed infants had large subcutaneous fat and minimal visceral fat. This may result in an increased insulin sensitivity pattern of growth in future36
Glyburide
In the treatment of GDM, metformin and glyburide were equally efficacious to insulin in blood sugar control. The only significant difference in outcome between the 2 drugs was that maternal weight gain with metformin was lower during pregnancy. Very few studies showed that the incidence of macrosomia and neonatal hypoglycemia is higher in babies of GDM mothers treated with glyburide37. In contrast to this, a meta-analysis showed that there is no consistent proof for rise in any adverse maternal or neonatal outcomes with the use of glyburide or metformin when compared to insulin use38
Oral agents are best in pregnancy because they are patient friendly and convenient, this inturn will improve patient compliance with treatment regimens. Oral agents do not require instruction at the time of initiation of therapy. On assessing the perinatal outcomes and glycemic control produced by oral hypoglycemic agents (OHAs), it was comparable to insulin. Insulin, inconvenient to use, needs ideal storage conditions and is costlier, all these factors makes it use difficult in developing countries. So, oral hypoglycemic agents should be regarded as safe remedy that that of insulin, which requires to be reserved as a second-line agent for patients in whom glycemic control is not achieved through oral drugs.34
Hence the main aim of this study is to compare maternal and fetal outcomes in women treated with diet only, metformin + diet, insulin + diet.

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