Gestational diabetes – an update

Dr Delia Bogdanet and Prof Fidelma Dunne give a comprehensive overview of the management of gestational diabetes mellitus, which is becoming an increasing issue in the modern world

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. This definition, however, does not exclude the possibility that the glucose intolerance might have been undiagnosed and may have antedated or begun at the same time with the pregnancy. So in 2014 the American Diabetes Association (ADA) are re-defined gestational diabetes as “diabetes diagnosed during pregnancy that is not clearly overt diabetes”.

Physiopathology

In normal pregnancy, maternal tissues become progressively insensitive to insulin.

Skeletal muscle and adipose tissue are the main whole-body glucose disposable sites. In normal pregnancy, insulin-mediated whole-body glucose disposal decreases by 50 per cent and in order to maintain a euglycaemic state, the woman must increase her insulin secretion by 200-250 per cent.

Some women have circulating immune markers (for example, anti-islet cell antibodies or antibodies to glutamate decarboxylase 65) that are diagnostic of evolving type 1 diabetes mellitus (T1DM); others have genetic variants that are diagnostic of monogenic forms of diabetes. These include genes for subtypes of maturity onset diabetes of the young (MODY) and maternally inherited diabetes.

GDM is a form of hyperglycaemia. Similar to other forms of hyperglycaemia, GDM is a disease of the pancreatic β cells, which do not produce sufficient insulin to meet the increased requirements of late pregnancy.

GDM is observed in obese as well as in lean women. However, the pathophysiology behind the disease is believed to differ between these groups. In obese women, the pathophysiology is primarily characterised by the pregnancy-induced insulin resistance being amplified by the already elevated pre-pregnant insulin resistance level. The elevated insulin resistance level is a known factor in the metabolic syndrome. In lean women, the same factors seem to play a role but a defect in the first-phase insulin response contributes to a larger extent. These defects culminate in a disruption of the action of insulin in maintaining glucose levels, resulting in maternal hyperglycaemia. Glucose is transferred via the placenta to the foetus. Maternal hyperglycaemia therefore stimulates a foetal hyperinsulinaemia to counter the excess placental glucose transfer.

Prevalence

GDM is increasing in prevalence in tandem with the dramatic increase in the prevalence of overweight and obesity in women of childbearing age. The criteria and cut-off values for the diagnosis of GDM are different worldwide. Depending on the screening strategies being used (universal or selective) and diagnostic criteria, estimated prevalence rates have significant variation – with an increasing trend over the last decades; and even within a country’s population, depending on the racial and ethical composition of the residents, the prevalence can vary. Globally, the prevalence of hyperglycaemia in pregnancy (GDM and manifest T2D in pregnancy) is estimated to be approximately 15 per cent; for Europe, the prevalence is 12.6 per cent. A recent paper has studied the GDM prevalence for high-risk women with a pre-pregnancy BMI ≥29kg/m² and has found a GDM prevalence ranging from the lowest 24 per cent in the UK up to the highest prevalence of 52 per cent in Denmark. In Ireland, the prevalence of gestational diabetes is 12.4 per cent.

Screening and diagnosis

Screening and diagnostic testing for GDM are very important in order to identify the women at risk of developing GDM and, in doing so, reducing or preventing the risk of adverse maternal and foetal complications.

Screening for GDM is usually done at 24-28 weeks of gestation because insulin resistance increases during the second trimester and glucose levels rise in women who do not have the ability to produce enough insulin to adopt this resistance.

Despite universal screening being the gold-standard, a large proportion of countries choose selective screening using parameters such as maternal age, previous GDM, previous large for gestational age babies, family history of diabetes, high pre-pregnancy BMI, belonging to an ethnic group associated with a high prevalence of GDM, hypertension, polycystic ovarian syndrome, women on long-term steroids, glucosuria or previously unexplained perinatal death. The argument for selective screening is that it helps concentrate medical resources on the patients with the highest risk of adverse events. However, by using selective screening, patients with GDM will be missed. Recent papers have shown that applying selective screening criteria would lead to up to 20 per cent of women with gestational diabetes being missed. Therefore, in 2011, the American College of Obstetricians and Gynaecologists (ACOG), ADA and Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) recommended universal screening because of the beneficial effect from screening, diagnosis and subsequent treatment. Also, what is important to note in the Avalos et al paper is that despite everybody being offered screening for GDM, only 75 per cent consented and of those who consented only 44 per cent presented for testing. This highlights the imperative need to improve compliance with the screening method either by facilitating access to it or by improving or changing the screening test. New biomarkers are now emerging.

In pregnancy there is a higher physiological turnover of erythrocytes, rendering glycosylated haemoglobin (HbA1c) inadequate as a diagnostic tool, because of underestimation of the average glucose level – a reduction of HbA1c is typical in normal pregnancy.

A fasting plasma glucose level >7.0mmol/l or a casual plasma glucose >11.1mmol/l meets the threshold for the diagnosis of diabetes, if confirmed on a subsequent day, and precludes the need for any glucose challenge. Otherwise, evaluation for GDM in women should follow one of the two following approaches.

One-step approach

Perform a diagnostic oral glucose tolerance test (OGTT). The one-step approach may be cost-effective in high-risk patients or populations.

Two-step approach

Perform an initial screening by measuring the plasma or serum glucose concentration one hour after a 50g oral glucose load (glucose challenge test [GCT]) and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT.

With either approach, the diagnosis of GDM is based on an OGTT. A variety of OGTTs have been applied, but a consensus regarding screening for and classification of GDM is yet to be achieved globally. However, a two-hour 75g OGTT at 24-28 weeks of gestation is now being recommended both by the European Association for the Study of Diabetes (EASD), International Association of Diabetes and Pregnancy Study Group (IADPSG), ADA and World Health Organisation (WHO).

In 2010 the IADPSG outlined new diagnostic criteria for GDM based on the knowledge achieved in the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study. This new guideline from the IADPSG was adopted by the WHO in 2013 and ADA in 2014 and is based on the risk of adverse pregnancy outcomes. The threshold for a positive test is exceedance of one of the following three plasma glucoses: Fasting plasma glucose ≥5.1mmol/L, one hour ≥10.0mmol/L, or two hours ≥8.5mmol/L. In comparison the WHO recommended threshold in 1999 was fasting plasma glucose ≥7.0mmol/L and in 1985 was fasting plasma glucose ≥7.8mmol/L.

Complications

Pregnancy complications – mothers

Women with GDM are at higher risk of hypertensive disorders including gestational hypertension and pre-eclampsia. In the HAPO study, 5.9 per cent had gestational hypertension and 4.8 per cent had preeclampsia. The HAPO study also found a direct correlation between Caesarean section rate and maternal glycaemia with an overall frequency of 23.7 per cent. In Ireland, the rates of complications amongst women with GDM were found to be as follows: 13.8 per cent developed maternal hypertension, 6.3 per cent developed pre-eclampsia, and 37.2 per cent underwent a caesarean section.

Pregnancy complications – infants

Macrosomia in new-borns of diabetic mothers is characterised by increased body fat. The HAPO study found that the percentage of body fat in new-borns, maternal glycaemia and foetal insulin levels estimated by cord C-peptide level were strongly positively correlated. Thus, maternal glycaemia is directly related to neonatal adiposity. Although rare, shoulder dystocia is a serious complication of childbirth. A clear association between increased foetal size and the risk of shoulder dystocia has been shown once the birth weight exceeds 4kg. In Ireland, 7.1 per cent of infants of mothers with GDM were born prematurely, 24 per cent were macrosomic, 23 per cent were large for gestational age and 26 per cent required neonatal intensive care admission.

Long-term complications

Women who are diagnosed with GDM are at high-risk of developing diabetes mellitus later in life. An estimated ~10 per cent of women with GDM have diabetes mellitus soon after delivery. The rest appear to develop diabetes mellitus at rates of 20-60 per cent within five-to-10 years after the index pregnancy in the absence of specific interventions to reduce their risk of diabetes mellitus.

The risk of diabetes mellitus in the mother after GDM is much higher than the risk of perinatal complications associated with GDM. Thus, GDM can be reasonably considered to be a form of pre-diabetes similar to impaired glucose tolerance in non-pregnant individuals.

The HAPO follow-up study analysed the data from 4,697 mothers, aged on average 41.7 years, and including 14.3 per cent who had experienced gestational diabetes, and their 4832 children, who were aged an average of 11.4 years. Nearly a third (30.2 per cent) of the children were overweight or obese according to the International Obesity Taskforce criteria and 11.2 per cent were obese. But the rates were higher if the children’s mothers had experienced GDM, at 39.5 per cent versus 28.6 per cent if they did not for overweight/obesity, and 19.1 per cent versus 9.9 per cent for obesity.

Gestational diabetes also affected the mothers’ longer-term outcomes, increasing their risk for dysglycaemia. Specifically, diabetes was present in 10.7 per cent of those who had experienced gestational diabetes versus 1.6 per cent who had not, and the same was true of impaired fasting glucose, at 30.8 per cent versus 9.7 per cent, impaired glucose tolerance, at 28.7 per cent versus 11.8 per cent, and any of the three measures, at 52.2 per cent versus 20.0 per cent. In Ireland, 25.9 per cent of women with previous GDM will develop glucose abnormalities post-partum compared to women with normal glucose tolerance during pregnancy who will develop glucose abnormalities post-partum in only 3.6 per cent of cases.

All women with GDM should receive nutritional advice, by a registered dietitian when possible. Individualisation of medical nutrition therapy (MNT) depending on maternal weight and height is recommended. MNT should include the provision of adequate calories and nutrients to meet the needs of pregnancy and should be consistent with the maternal blood glucose goals. Compared to diet alone, exercise with dietary modifications has been found to lead to improved glycaemic control in one study. The proposed mechanism for such an improvement in glycaemic control is heightened sensitivity of peripheral tissues to insulin. Diet therapy has been focused on carbohydrate restriction. Evidence from the randomised trials, however, supports the idea that women with GDM tolerate higher complex carbohydrate diets. In fact the data from randomised controlled trials would suggest a diet that liberalises complex carbohydrates (using higher fibre and lower glycaemic index carbohydrates) and limits saturated fats may be optimal in improving glycaemia and preventing further insulin resistance. The recommended weight gain during singleton pregnancy is dependent on pre-pregnancy BMI: 12.5-18kg of weight gain for underweight women (BMI <18.5kg/m²); 11.5-16 kg for normal weight (BMI 18.5-24.9kg/m²); 7-11.5kg for overweight (BMI 25-29.9kg/m²), and 5-9kg for obese (BMI ≥30.0kg/m²).

As with screening and diagnostic recommendations, glucose testing and treatment goals differ among guidelines. All sources agree that elevated postprandial glucose is more predictive of negative outcomes, especially foetal macrosomia, compared with pre-prandial levels, with some indicating a stronger correlation with one-hour compared with two-hour postprandial levels. It is generally recommended that patients self-monitor seven times per day: fasting glucose and before every meal (goal <5.3mol/L) and postprandial glucose one hour (goal <7.8mol/L) after eating.

Pharmacological intervention

Pharmacological intervention in the management of GDM is usually employed when women fail to meet established goals with conventional therapy of diet and exercise. It is also indicated when elevated fasting glucose levels occur while on conventional therapy, because dietary modification has limited effect on these levels. Although most women achieve adequate glycaemic control with conventional therapy, 30-40 per cent require the addition of pharmacologic therapy at some point during their pregnancies. The pharmacological options in this case include insulin or oral hypoglycaemic agents (metformin and glyburide).

Insulin is the pharmacologic therapy that has most consistently been shown to reduce foetal morbidities when added to MNT. Selection of pregnancies for insulin therapy can be based on measures of maternal glycaemia with or without assessment of foetal growth characteristics.

The type and timing of insulin should be chosen based on the specific blood glucose elevation. If the fasting glucose is greater than 5.1mol/L then basal insulin, long-acting insulin analogue, or neutral protamine Hagedorn (NPH) should be started before bedtime.

In cases where glucose level is elevated following a meal, rapid-acting insulin or regular insulin should be prescribed before that specific meal, beginning with two-to-four units, or a dose of one unit per 10-15g of carbohydrates. If both fasting and postprandial glucose levels are elevated, a four-injections-per-day regimen ‘basal and mealtime insulin regimen’ should be prescribed.

When deciding how to dose insulin in pregnancy, the recommendations are not specific to GDM. The general principles for dosing insulin in pregnancy apply to pre-gestational and gestational diabetes. Although insulin sensitivity fluctuates throughout pregnancy, by the time insulin is needed for GDM, patients are often at the end of their second trimester or even in their third trimester. Insulin resistance increases throughout pregnancy, so the total daily dosing requirements are usually 0.8-0.9 units of insulin per kg of body weight. In a morbidly obese woman, the initial doses of insulin may need to be increased to 1.5-2.0 units/kg.

Insulin therapy decreases the frequency of foetal macrosomia and the risk of perinatal morbidity. Positive history of diabetes mellitus in a first-degree relative and multiple abnormal values in the OGTT were strongly found to predict the need for insulin management in women with GDM. Measurement of the foetal abdominal circumference early in the third trimester can identify a large subset of infants with no excess risk of macrosomia in the absence of maternal insulin therapy.

Metformin is another oral hypoglycaemic agent considered a potential substitute for insulin in GDM management. In a randomised controlled trial involving women with GDM, the use of metformin, whether alone or with supplemental insulin, was not associated with increased perinatal complications compared to insulin alone. Meanwhile, a 2013 meta-analysis found that metformin is comparable to insulin regarding glycaemic control and neonatal outcomes. In another recent study, metformin use was associated with similar desirable outcomes when compared to MNT and insulin use; its use was not associated with a higher risk of maternal or neonatal complications.

Post-partum follow-up

The main emphasis of post-partum care should be the assessment of the future risk of diabetes mellitus and mitigating that risk. Glucose tolerance testing one-to-four months postpartum is useful for the identification of additional women with diabetes mellitus and in stratifying the one-to-five-year risk of diabetes mellitus. In women who do not have diabetes mellitus at postpartum testing, the risk increases linearly for at least the first five-to-10 years, during which 30-50 per cent of women develop diabetes mellitus.

Several studies have looked at ways to prevent the development of type 2 diabetes (TDM) in women with previous GDM. All these studies highlight and prove the importance of consistent, sustainable postpartum lifestyle change and interventions, through diet and exercise in preventing glucose abnormalities in later life. The purpose of these studies was to show that lifestyle interventions could prevent or at least postpone the development of T2DM. These interventions should be easily adopted and implemented in primary healthcare. A very important observation in these studies was that the intervention needs to be individualised, continuing and performed by skilled individuals in order to be effective.

References on request