Gestational diabetes mellitus (GDM) is defined as glucose intolerance of variable severity, with onset or first recognised during pregnancy1. This definition includes women whose blood glucose goes back to normal after giving birth, those with undiagnosed type I or type II diabetes and also those with monogenic diabetic2. GDM is believed to complicate approximately 1% to 5% of all pregnancies and is associated with increased foetal and maternal morbidity and mortality1. The prevalence ranges from less than 1% to more than 10% due to the different populations or ethnic groups being studied and lack of uniformity on diagnostic test employed1. Women from Indian subcontinent have an increased prevalence rate of GDM by eleven fold whereas those from South East Asia have eight fold increased rate3. This is followed by women from Arab or Mediterranean with six fold and Afro-Carribbean women with three fold3.

The pathophysiology of gestational diabetes mellitus includes increase in maternal insulin resistance, autoimmune β-cell dysfunction and genetic abnormalities which causing impaired insulin secretion4. Progression of insulin resistance normally starts near the mid-pregnancy throughout the third trimester and progresses to resistance level seen in Type II diabetes4. There are two type of insulin resistance namely physiological insulin resistant and chronic insulin resistant with β-cell dysfunction. It has been suggested that physiological insulin resistance is contributed by combination of increased maternal adiposity and effects of placental growth hormones4. A study revealed the defects of postreceptor in the insulin-signalling pathway of skeletal muscle and adipose tissue has caused the insulin sensitivity reduction in pregnancy5. The alterations in the pathway reduce the insulin-mediated glucose uptake in skeletal muscle which is a major tissue for glucose disposal5. The increase in physiological insulin resistance and alterations in glucose metabolism are believed been influenced by placental growth hormones. This is proven when resistance abates soon after labouring in women with normal glucose tolerance6. Chronic insulin resistance is a condition where patients have β-cell dysfunction which is presented before pregnancy and exacerbated during pregnancy due to some physiological changes6. Chronic insulin resistance occurred mostly in women with GDM and this had been demonstrated in a study where normal women have higher insulin sensitivity than those with GDM after physiological insulin resistance abates4. It is also believed that obesity play a role in developing insulin resistance since GDM women tend to be obese6.

Among the women diagnosed with GDM, a minority of less than 10% of them have presence of cytoplasmic islet cell antibodies and anti-GAD antibodies in their circulation6. These are the markers used to identify the individuals who develop autoimmune diabetes namely Type I diabetes. Patients with autoimmune destruction of pancreatic β-cells will then have inadequate amount of insulin which leads to hyperglycaemia. This subtype of patients most probably will experience rapid metabolic deterioration after pregnancy due to the autoimmune destructive condition6. Besides autoimmune β-cells destruction, genetic abnormalities caused by autosomal and mitochondrial DNA mutations also contributed to less than 10% of GDM6. The autosomal mutation, for instance maturity-onset diabetes of the young (MODY) has a dominant inheritance pattern whereas mitochondria DNA mutations has maternal inheritance pattern4, 6. Both of these monogenic forms of diabetic have a younger age onset than non-immune type of diabetes and the patients do not suffer from obesity and insulin resistance6. The genes involved in the monogenic diabetes appear to posses a crucial influence on β-cells regulation which severe enough resulting hyperglycaemic if mutation occurs even with the absence of insulin resistance6.

3.0 Implications

3.1 Maternal implications

GDM may implicate either immediate or long term mortality on pregnant women. Studies have demonstrated that GDM has complicated pregnancy by increasing duration of maternal hospitalization, caesarean delivery and also preeclampsia in pregnant women7, 8, 9. Caesarean delivery incidence is increased in GDM pregnancies in order to avoid birth trauma7.

Women with GDM are also at increased risk to develop type II diabetes with trials showed that 30% to 50% former GDM women developed diabetes at 3 to 5 years after their delivery10. Women who have GDM with higher BMI are more susceptible to diabetes development. This is demonstrated by a study where approximately 60% of obese women and 30% of lean women during pregnancy have 15 years of prevalence in Type II diabetes11. The study is supported by other studies where maternal obesity plays an important role in developing diabetes later in life12.

A considerable number of women with prior GDM were found to share some characteristics of those suffered from metabolic syndrome like elevated triglyceride levels, glucose intolerance, obesity and HDL cholesterol reduction. Women who are diagnosed with impaired glucose tolerance at 6-12 weeks postpartum showed increased triglycerides level and decreased HDL cholesterol as well as systolic blood pressure >140mmHg compared to those with similar BMI and normal glucose tolerance13. Atherosclerosis which is known to be contributed by inflammatory responses also studied in women with GDM with findings showed that hsCRP and interleukin-6, both are inflammatory mediators, were respectively higher in GDM women after 3 months postpartum than in normal subjects14. Studies of women prior GDM on insulin resistance and factors in metabolic syndrome suggest that lipid abnormalities and inflammatory mediators significantly related to cardiovascular threat.

3.2 Foetal and neonatal implications

Offspring of mother with GDM have an increased risk of perinatal mortality as well as morbidity which involved hyperbirubinemia, hypoglycaemia, macrosomia, birth trauma, childhood risk of obesity and subsequently type II diabetes and cardiovascular disease15. Improper management of GDM women during pregnancy has contributed to a four fold increasing in perinatal mortality rates11. Approximately 20% of GDM pregnancies are found to be complicated by macrosomia which defined as foetus weight lies above the 90th percentile of gestational age or more than 4000g15, 16. Maternal nutrition is a crucial factor in foetal growth. Excess foetal growth is caused by diabetic intrauterine environment since glucose passes through placenta but maternal insulin unable to cross the placenta17. Besides, increased glucose load in foetal also promotes the growth hormone under influence of developing foetal pancreas and further encourages foetal growth and adiposity17. As a result, shoulder dystocia, a condition where one of the shoulders being stuck behind mother’s pelvic bone, preventing the birth of baby’s body can occur if foetal weight is above 4000g18. The chance of developing shoulder dystocia is even increased by two to six folds if the growth of the trunk and shoulder is not proportionate18.

A study indicated that offspring of GDM women have increased body fat when compared with same weight offspring of controlled healthy women19. Offspring of women with GDM are also found to be on 30% heavier than expected according to their height20. The study also evaluated that there is a strong relationship between pancreas cell activation in diabetic intrauterine environment and childhood obesity, which then predisposes to obesity20. Maternal insulin insensitivity is then believed to associate with foetal overgrowth, predispose to childhood obesity and glucose intolerance. Cardiovascular abnormalities can be another implication on offspring of women with GDM. Diabetes is a known risk factor for cardiovascular disease and this issue is evaluated and examined in offspring of diabetic pregnancies. The results significantly showed that offspring of the diabetic pregnancies has higher systolic and mean arterial blood pressure, endothelial dysfunction markers as well as cholesterol level compared to offspring of healthy mothers20.

4.0 Screening and diagnosis

All pregnant women will undergo universal screening for GDM between 24-28 weeks of gestation and those with high risk of GDM development should perform the screening at first trimester21. Women with high risk of developing GDM refer to those who fulfil one or more risk factors. For instance, over 35 years old, previously diagnosed with GDM or with macrosomic, from high risk populations like American Indian, South-East Asian and Arab, obesity which BMI ≥ 30kg/m², diagnosed with polycystic ovary syndrome and first degree relative to diabetes3, 21. The screening test is called oral glucose challenge test (OGCT) and carried out where the pregnant women were given a sugary beverage with 50g glucose load to drink21. After an hour, plasma glucose is measured and if the reading is ≥10.3 mmol/L, GDM is diagnosed21. If the plasma glucose reading is <7.8 mmol/L, the subject should be reassessed during subsequent trimesters if she fulfils multiple risk factors21. The subject’s plasma glucose that lay 7.8-10.2 mmol/L will ask to undergo another oral glucose tolerance test (OGTT) 21. 75g of glucose load will be given and blood samples are tested at 0, 1, and 2 hour21. The fasting plasma glucose should be ≥5.3 mmol/L, one hour plasma glucose should be ≥10.6 mmol/L and two hour plasma glucose should ≥8.9 mmol/L21. If the subject has found to exceed two criteria out of three, she is diagnosed with GDM21. Those meet one out of three criteria are diagnosed with impaired glucose tolerance of pregnancy21.

Figure 1: Screening and diagnosis of gestational diabetes mellitus21.

*Other diagnostic method like using 100-g OGTT may be used.

1hPG = 1-hour plasma glucose 2hPG = 2-hour plasma glucose

FPG = fasting plasma glucose GDM = gestational diabetes mellitus

GDS = Gestational Diabetes Screen IGT = impaired glucose tolerance

OGTT = oral glucose tolerance test

5.0 Managements

5.1 Medical Nutrition Therapy (MNT) and physical activity

Women with GDM should receive a nutritional counselling by a registered dietician or qualified individuals who are experienced in managing patients with GDM22. The food plan that is designed for a particular individual not only needs to fulfil the minimum nutrient requirement for pregnancy but also being able to maintain glycaemic target that have been established22. The individualised food plan is designed based on patient’s body habitus, pre-pregnancy weights and physical activities22. The food planning should emphasise on moderate carbohydrate restriction in order to prevent ketosis and may not always emphasise on low-fat foods since foetus needs cholesterol22. Medical nutritional therapy is considered as the primary therapy for 30-90% of women with GDM since studies have proved that GDM women who have undergone MNT had infants with lower birth weight, less macrosomia, and reduced perinatal complications22. Physical activities should also be encouraged since it is adjuvant in maintaining glycaemic target22. Regular aerobic exercises also demonstrated to lower the fasting and postprandial glucose in women who previously diagnosed with GDM22.

5.2 Self-monitoring blood glucose (SMBG)

Self monitoring of blood glucose is performed during pregnancy by using a glucose meter and testing strips. It is well-tolerated by most women and is useful to evaluate and adjust patients’ therapy such as medical nutritional therapy and insulin therapy 23, 24. SMDG is crucial to check for asymptomatic hyperglycaemia as well as hypoglycaemia. Pregnant women with GDM should check their blood glucose three or more times each day throughout their pregnancies23. Nocturnal hypoglycaemia has been an issue during pregnancy for those who are on insulin therapy24. Therefore, self testing during the night is necessary.

5.3 Pharmacological treatment

5.3.1 Insulin

When the blood glucose exceeded target goals on two or more occasions within two weeks when patients are on MNT, this indicated that the standard nutritional therapy is not sufficient to maintain the glycaemic target23. Insulin should be started especially those with suspected macrosomia since it has promising benefits on foetal when added with MNT25. Human insulin is most commonly used as it is least immunogenic and reported to improve pregnancy and infants outcomes when compared to other preparations like mixed beef-pork insulins26. Besides human insulin, an analogue lispro, which is rapid-acting insulin, has found to be more efficacious in controlling blood glucose of GDM women than human insulin26. Lispro has found to improve postprandial glucose with less hypoglycaemic episodes26. Insulin aspart, another short-acting analogue, has also found to lower postprandial glucose significantly better than human insulin and effectively control postprandial glycaemic is GDM women26. Both analogues have been investigated in pregnancy with no evidence of tetragenesis was found26. There are also long-acting insulin analogues namely insulin glargine and insulin detemir were found26. However there is limited investigation on the clinical effectiveness of these analogues especially when used in pregnant women. Insulin dosage regimes should be adjusted according to patient’s acceptability as well as glycaemic profile. Self-monitoring of blood glucose is required to maximise glycaemic control and prevent hypoglycaemic episodes. Generally, insulin has found to be safe in pregnant women due to the fact that it has large molecular weight and is unable to cross placenta thus affecting foetus27. However, there has been an issue on human insulin antibody production in women with GDM, and the antibody complex could affect the foetus growth27. Moreover, insulin injections also account for several downsides such as patients’ discomforts and cost.

5.3.2 Oral hypoglycaemic agent

Most of the oral hypoglycaemic agents are not advised in treating women with gestational diabetes. This is due to the fact that the drug administered may cross the placenta and affect the foetus. Oral hypoglycaemic agents are generally categorised as insulin secretagogues, insulin sensitizers and α-glucosidase inhibitors28. Insulin secretagogues include sulfonylurea and meglitinide, both will stimulate insulin secretion by binding to different receptors at β-cells28. Sulfonylureas can cause hypoglycaemia while suppressing hepatic glucose production and improve β-cells to produce insulin28. This class of drugs has found to cause 20% reduction in plasma glucose and work best in those who have normal and slightly increase body weight28. Glyburide, a second generation of sulfonylurea, acts as a longer acting agent, has found to treat hyperglycaemia successfully in controlled trials for pregnant women with no evidence of risk found on human28, 29. In a study where the use of glyburide was compared with insulin therapy, the outcomes of these two groups showed comparable results and when the insulin level of cord plasma was tested, no significant differences was noted for glyburide29.

Insulin sensitizers include biguanides and thiazolidinediones, both are useful in insulin resistance condition by enhancing peripheral insulin action and stimulating glucose uptake28. Since these drugs do not secret insulin, hence hypoglycaemia would not be an issue in patients taking these drugs. Metformin is from biguanide class and used commonly in obese, insulin resistant patients since it would not promote fat deposition. In addition, metformin is used in patients with polycystic ovary syndrome to treat their infertility28. Studies found that significant amount of metformin was found in cord blood of foetus, concluding that metformin can cross the placenta with unknown effects on foetus28. Rosiglitazone is a drug from thiazolidinedione drug class and since there are few studies on this drug especially on pregnant women, it is not recommend in treating women with gestational diabetes. Thiazolidinedione drugs also found to have other severe effects like weight gain and fluid retention which will predispose to heart failure if diuretics are not useful28.

α-glucosidase inhibitors act by slowing the glucose absorption at upper gastrointestinal tract, thus maintaining postprandial glucose28. Currently, there are only a few studies have been conducted on usage of this class of drugs on pregnant women and most studies reviewed the gastrointestinal side effects of α-glucosidase inhibitor28. This class of drugs generally appeared to be safe but are not well tolerated due to the gastrointestinal side effects.

5.4 Prenatal Surveillance

In order to optimise the outcomes for pregnant women with gestational diabetes, prenatal surveillance is necessary. Women with GDM should monitor foetal movements at 28 weeks of pregnancy and should report immediately if there is any reduction in foetal movements23. Prenatal surveillance can be delayed until weeks 40 if the hyperglycaemic is controlled using MNT only23. For women who are on pharmacological treatment such as insulin therapy, non-stress testing should be encouraged after week 32 of the pregnancy30. Ultrasound can be used to detect abnormalities or macrosomia in foetus30.

5.5 Labour and Delivery Management

Women with gestational diabetes are found to have greater risk of giving birth to excessive grown babies and may be complicated by shoulder dystocia30. Therefore, ultrasound can be used within 2 weeks of delivery to estimate the foetal weight and decide whether a caesarean delivery option is better in order to prevent shoulder dystocia23, 30. A study has been performed where caesarean delivery was recommended if the estimated foetal weight (EFW) was above 4250g and labour induction was recommended if the EFW is 90th percentile. The results showed that the incidence of shoulder dystocia has decreased significantly by 11%30.

5.6 Postpartum follow-up

All women with prior gestational diabetes have an approximately 50% risk of developing type II diabetes within the next 10 years23. Their chances of developing type II diabetes even have increased up to 80% if impaired glucose tolerance was developed after delivery23. Hence, appropriate counselling and follow up are important after delivery. Breastfeeding should be encouraged due to the fact that it may minimise the insulin resistance and decrease maternal progression to diabetes 21, 23. Women who gain much weight during pregnancy are advised to keep fit and if possible maintain to their pre-pregnancy weight. Glucose tolerance testing should be performed at week 6-12 on women who do not develop diabetes immediately after delivery23. Furthermore, infants of women with gestational diabetes also associated with higher risk of obesity and subsequently to diabetes thus counsel on healthy lifestyle is crucial for them.

6.0 Recommendations

The case scenario is regarding a 27 years old pregnant woman with gestational diabetes. The patient should be first started on medical nutritional therapy which her meal plan should be designed just for her by an experienced dietarian. Patient should be advised to follow the meal plan and perform some exercises in order to achieve her glycaemic control. If patient’s blood glucose was in good controlled with her pre and postprandial glucose levels were satisfied with fasting is within 3.8-5.2 mmol/L and two hour postprandial within 5.0-6.6 mmol/L and there is no evidence of foetus excessive growth, she can then be managed as normal pregnant women21, 23, 31. On the other hand, if patient’s blood glucose is not well controlled after a trial of dietary intervention for 2 weeks, with fasting glucose level exceed 6mmol/L, 2 hour postprondial levels exceeds 7mmol/L and also an evidence of macrosomia from ultrasound, insulin therapy should be added in31.

Insulin will be given by subcutaneous injection and the doses need to be adjusted and assessed frequently. The dose of insulin generally needed to be increased in the second and third trimesters of pregnancy32. Short-acting insulin, insulin Lispro can be the choice for this patient. This is because Lispro has no evidence of tetragenesis and is found to be more efficacious to control postprandial glucose with less hypoglycaemic eposodes26. In addition, insulin Lispro was found to have no significant differences with regular insulin in terms of maternal and foetal outcomes. Patients’ satisfaction was also significantly higher for insulin Lispro with p<0.05 than regular insulin. When patient is on insulin therapy, it is important for them to monitor their own glucose level especially at night to prevent nocturnal hypoglycaemic.

If patient was unable to tolerate insulin therapy due to the invasive pain, a non-invasive alternative can be recommended to this patient. The non-invasive alternative is glyburide, a long acting sulfonylurea. This drug acts by affecting the ATP dependent potassium channels, thus inhibiting potassium efflux to occur33. Pancreatic β cells are then stimulated by cellular depolarisation to secret insulin33. Glyburide is usually administered once daily since the terminal half- life is 10 hours, promising a 24-hour of glucose controlling effect29. Various studies have been focused on the usage of this drug on pregnant women and it was found that glyburide would not cross the human placenta in contrast to other oral hypoglycaemic agent29. A trial evaluated that there is no significant differences in mean maternal concentration, macrosomia, foetal abnormalities and neonatal intensive care admission between two groups of GDM women who treated with insulin and glyburide29. Therefore, glyburide can be an alternative method to treat gestational diabetes. However insulin therapy remained to be the first option when treating the patients because those who are unable to respond to glyburide treatment were switched to insulin therapy in the previous trial and this accounted for 4% of the glyburide group29.

Metformin can be used as another option if glyburide could not control patient’s blood glucose. Metformin was found to be beneficial in patients who are obese since it reduces the fat deposition, unlike glyburide34. The MiG (Metformin in gestational diabetes) study reviewed that this non-invasive method is more acceptable than insulin therapy and would not result in hypoglycaemic34. Besides, the loss of weight for subjects who used metformin was highly significant34. However, the fact that 40% of the women who treated with metformin required supplementary insulin therapy for glycaemic control concluded that insulin therapy is nevertheless the best option for this patient34 if patient can tolerate with the discomfort.

Besides the pharmacological treatment, it is critical that patient carried out the prenatal surveillance to improve the pregnancy outcomes. Counselling on the delivery option should be given if macrosomia is detected from ultrasound to minimise the infant injury. The patient should also be encouraged on breastfeeding after labouring. Maintaining healthy diet is essential and they should be re-evaluated postpartum since they are at higher risk of developing Type II diabetes.