Bee Yong Mong MBBS, MRCP (UK), Peter Eng Hsi Ko MRCP, FAMS
Department of Endocrinology, SGH

* Presented at the SGH Hospital-wide Monthly Clinical Meeeting on 14 August 2004.

Gestational diabetes mellitus (GDM) is one of the major medical complications of pregnancy. It has been recognised for more than three decades, but there is still a wide diversity of opinion regarding detection and clinical management. There is convincing evidence that mild maternal hyperglycaemia is a risk factor for foetal morbidity and failure to recognise and treat the condition will result in unnecessary morbidity in some pregnancies. This article reviews the current literature on GDM, focusing on the screening, diagnosis and treatment of GDM and discusses the role of insulin analogues and oral hypoglycaemic agents. The importance of postpartum care of women with GDM as well as the preconception care of women with diabetes will also be discussed.

Keywords: gestational diabetes mellitus, pregnancy, insulin

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of varying degrees of severity, with onset or first recognition during pregnancy.¹ The definition applies whether insulin or only diet modification is used for treatment and whether or not the condition persists after pregnancy. It does not exclude the possibility that the glucose intolerance may have antedated the pregnancy. This definition does not apply to pregnant women with previously diagnosed diabetes (i.e. pre-gestational diabetes).

Approximately 7% of all pregnancies are complicated by GDM.² The prevalence rate in the United States has varied from 1.4 to 14% in different studies.^3-7 Our local incidence of GDM has been reported to be from 1.3 to 13.1%, depending very much on the diagnostic criteria used and the study cohort.^8,9 The differences in screening programmes and diagnostic criteria make it difficult to compare frequencies of GDM among various populations.

Based on available data, King predicted that the prevalence of GDM varied in direct proportion to the prevalence of type 2 diabetes in a given population.¹⁰ The prevalence of diabetes mellitus among Singapore residents in 1992 was 8.6%.¹¹ A study by Tan et al reported a GDM incidence of 8.6% (spot on) based on data collected in the early 1990s.¹²

Ethnicity has been proven to be an independent risk factor for GDM. Gunton et al showed that Asian women were more likely to have GDM than Caucasian woman (31.7% and 14% respectively, P = 0.02) despite having a lower body mass index (BMI).¹³

The traditional and most often reported risk factors for GDM are high maternal age, weight and parity, previous delivery of a macrosomic infant and family history of diabetes. These and other reported risk factors are summarised in Table 1.¹⁴

Table 1. Summary of reported risk factors for GDM.14

Pregnancy is a diabetogenic state manifested by insulin resistance and hyperinsulinaemia. The resistance arises from the placental secretion of diabetogenic hormones including growth hormone, corticotrophin-releasing hormone, human placental lactogen, and progesterone. In addition to the direct hyperglycaemic effects of some of these hormones, a post-receptor defect also may contribute to the decline in insulin action.^15-17 Recent studies have shown that leptin and tumour necrosis factor-alpha are the strongest predictors of pregnancy-associated insulin resistance, far greater than previously suggested for gestational hormones, including human placental lactogen and steroids.^18,19

As pregnancy advances, the increasing tissue resistance to insulin creates a demand for more insulin. Appropriate metabolic adaptations occur in normal pregnant women to ensure that the balance between insulin resistance and insulin supply is maintained. GDM occurs when a woman’s pancreatic function is not sufficient to overcome the insulin resistance created by the anti-insulin hormones and the increased fuel consumption necessary to provide for the growing mother and foetus.

More recently, Radaelli et al reported that GDM elicits major changes in the expression profile of placental genes with a prominent increase in markers and mediators of inflammation.²⁰ Therefore, the foetus of a diabetic mother develops in an inflammatory milieu. These changes in the expression of specific placental genes may be a leading cause of adverse foetal programming.

The diagnosis and treatment of GDM are important because of the association of hyperglycaemia, especially when severe, with maternal and foetal morbidity.

There is an increased frequency of hypertensive disorders in women with GDM. The data are most convincing for an association with preeclampsia.^21-23 A number of studies have investigated whether pregnancy-induced hypertension is more common in women with GDM, but no consensus has been reached.²⁴

The dominant antepartum clinical risks of GDM are to the foetus. Macrosomia (neonatal birth weight ³ 4.5kg) and associated complications of labour and delivery are the most frequent and serious types of morbidity.

Foetal macrosomia may affect up to 40% of the offspring of pregnancies complicated by GDM.²⁵ Hod et al observed macrosomia in 17.9% of pregnancies complicated by GDM despite treatment compared with 5.6% of control subjects.²⁶ Macrosomia is also associated with increased risk of birth injuries, such as shoulder dystocia and brachial plexus injury.²⁷

Neonatal metabolic complications, such as hypoglycaemia, hyperbilirubinaemia, hypocalcaemia and polycythaemia, have been reported with varying frequency. The risk appears to increase with the degree of maternal hyperglycaemia.

Some studies have reported an increased frequency of major congenital anomalies, but the increase appeared to be limited to infants whose mothers had severe hyperglycaemia.^28,29 Schaefer et al reported a doubling of the rate of major anomalies with a fasting glucose level > 6.7mmol/l.³⁰

The American Diabetes Association (ADA) and the American College of Obstetricians and Gynecologists (ACOG) recommend limiting screening to women with risk factors for GDM.^31,32 Specifically, the ADA suggests that it is not cost-effective to screen women who are below 25 years of age, have a normal body weight, no family history of diabetes, no history of abnormal glucose tolerance and no history of poor obstetric outcome. In a recent multi-centre Danish study to prospectively evaluate a screening model for GDM on the basis of clinical risk indications, 5235 consecutive pregnant women, with and without clinical risk factors, underwent diagnostic testing with a 2-hour 75g oral glucose tolerance test (OGTT).³³ The researchers concluded that both screening and diagnostic testing could be avoided in two-thirds of all pregnant women if testing were only performed in women with risk factors.

On the contrary, some authors believe that identification and treatment of gestational hyperglycaemia can improve pregnancy outcome and that selective screening approaches are cumbersome and not sufficiently sensitive. Moses et al showed that with selective screening, 10% of women with gestational diabetes would have been missed.³⁴ These women had pregnancy outcomes similar to those with gestational diabetes.

Thus, several practical options for screening exist. The choice of technique is not as important as the decision to screen, since the asymptomatic hyperglycaemia of GDM will not be apparent without screening.

Locally, selective screening for GDM is adopted.³⁵ Women with risk factors for GDM are evaluated for glucose intolerance with an OGTT.

Screening is optimally performed at 24 to 28 weeks of gestation.³⁶ However, women with clinical characteristics consistent with a high risk of GDM should undergo glucose testing as soon as it is feasible.² If they are not found to have GDM at the initial screening, they should be retested between 24 and 28 weeks of gestation.

Table 2 shows the most commonly recommended screening and diagnostic criteria for GDM.

These are the criteria endorsed by the ADA and the World Health Organization (WHO).^1,37,38

Table 2. Criteria for the diagnosis of gestational diabetes mellitus.

According to the ADA guidelines, a fasting plasma glucose level ³ 7.0mmol/l or a casual plasma glucose ³ 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.² In the absence of this degree of hyperglycaemia, further evaluation will be required. This evaluation should follow one of two approaches:

1. In the one-step approach, a diagnostic OGTT is performed without prior plasma glucose screening.
2. In the two-step approach, an initial 50g oral glucose load (glucose challenge test [GCT]) is given and plasma glucose is measured one hour later. A glucose threshold value of > 7.8mmol/l is considered abnormal and will identify approximately 80% of women with GDM. The yield is further increased to 90% using a cutoff of > 7.2mmol/l.² Women with an abnormal value are then given a 100g 3-hour OGTT. Two or more of the plasma glucose concentrations must be met or exceeded for a positive diagnosis.

The ADA has also endorsed a 2-hour 75g OGTT for diagnosis of GDM, although it has different criteria for a positive test (Table 2). However, this test is not as well validated for detection of at-risk infants or mothers as the 100g OGTT.

Most of the world uses some modification of the diagnostic criteria of the WHO for diabetes, which is based on a 2-hour 75g OGTT.^37,38 Diabetes, whether gestational or not, is diagnosed if the fasting plasma glucose level is ³ 7.0mmol/l or the 2-hour plasma glucose is ³ 11.1mmol/l. However, it has generally been recognised that a 2-hour plasma glucose level of 11.1mmol/l is too high for safety during pregnancy. Gestational impaired glucose tolerance (2-hour plasma glucose level of ³ 7.8mmol/l) has therefore been arbitrarily included in the definition of GDM and should be treated in the same way as GDM. The WHO criteria have the advantage of employing a test that is identical to the test used in women when they are not pregnant, making the results directly comparable.

Locally, GDM is diagnosed with a 75g OGTT based on the WHO criteria.³⁵

There is currently a multi-centre international trial (the Hyperglycaemia and Adverse Pregnancy Outcomes [HOPA] study) underway to correlate the results of the 75g OGTT with pregnancy outcomes.³⁹ These data should provide a basis for the development of international agreements on the best criteria for diagnosing GDM and the best protocol for identifying women at risk.

All women with GDM need to perform self-monitoring of blood glucose to guide the treatment decisions about insulin therapy. There are no uniform recommendations for the frequency of serum glucose monitoring or an ideal "target range" for glycaemic control.

Various methods of glucose monitoring have been proposed, including the measurement of fasting, preprandial, postprandial, and mean 24-hour blood glucose concentrations.

Postprandial hyperglycaemia has been shown to be more closely related to foetal macrosomia than preprandial hyperglycaemia in pregnancies complicated by preexisting diabetes.^40,41 De Veciana et al showed that women monitored after meals lowered their HbA1c to a greater degree and had a lower risk of neonatal hypoglycaemia, macrosomia, and caesarean delivery.²⁵

Moses et al compared the outcome of 166 pregnancies complicated by GDM in women who tested 1-h postprandially (with a target glucose level of < 8.0mmol/l) to the outcome of pregnancies of 101 women who tested 2-h postprandially (with a target glucose level of < 7.0mmol/l).⁴² They showed that monitoring either 1-h or 2-h postprandially led to similar outcomes, suggesting that women could choose the most convenient time for their postprandial monitoring.

Home blood glucose monitoring with memory-capable metres appears superior to monitoring with visually read strips in identifying women whose blood glucose concentrations remain elevated while they are receiving dietary therapy.⁴³

The measurement of fasting, preprandial and postprandial glucose levels has an important limitation, in that it provides only single values during the day and not a longitudinal daily glycaemic profile. Yogev et al showed that continuous glucose monitoring could diagnose high blood glucose levels and nocturnal hypoglycaemic events that are unrecognised by intermittent blood glucose monitoring.⁴⁴ This could serve as a useful tool for the long-term management of diabetic pregnancies.

The Fourth International Workshop Conference on Gestational Diabetes Mellitus recommended maintaining blood glucose concentrations at < 5.3mmol/l before meals and < 7.8 and 6.7mmol/l 1 and 2 hours, respectively, after meals.1 Some clinicians have used more strict glycaemic targets; fasting blood glucose concentrations < 5.0mmol/l and one-hour postprandial blood glucose concentration < 6.7mmol/l.⁴⁵

A useful rule-of-thumb is to maintain fasting glucose < 5.0mmol/l, pre-meals glucose < 6.0mmol/l, 2-hour postprandial glucose < 7.0mmol/l and 1-hour postprandial glucose < 8.0mmol/l.

Good, but not extreme, glycaemic control has the most beneficial impact on foetal weight. Langer et al found that extreme glycaemic control was associated with a doubling risk (20%) of small-for-gestational-age infants.⁴⁶ In a systematic review comparing outcomes following tight versus very tight control of gestational diabetes, Walkinshaw found that maternal hypoglycaemia was more common among women whose diabetic control was very tight compared to tight control but there was no difference detected in perinatal outcome between the groups.⁴⁷ Hence, there appears to be no clear evidence of benefit from very tight glycaemic control for GDM patients.

A stepwise approach to GDM treatment should be adopted once the condition is diagnosed. Instruction in proper diet and exercise is the foundation for treatment. If these strategies alone are unsuccessful, then pharmacotherapy should be initiated.² Insulin remains the standard medication to treat diabetes in pregnancy, but many other possible treatment strategies are being evaluated. The treatment strategy should be designed to prevent macrosomia.

Nutritional therapy is very important for both the mother with GDM and her infant. The optimal dietary prescription provides the caloric and nutrient needs to sustain pregnancy but does not cause postprandial hyperglycaemia.

There are no randomised controlled trials specifically focused on the development of an optimal diet for women with GDM. The meal plan that the ADA supported, which was composed of >55% carbohydrates and aimed to produce 35kcal/kg of present pregnant weight, not only caused excessive weight gain but also resulted in severe postprandial hyperglycaemia.⁴⁸

One "euglycaemic" diet which has proven to provide the needs of pregnancy and not result in excessive weight gain or hyperglycaemia consists of 30kcal/kg of present pregnant weight for normal weight women, 24kcal/kg for overweight women and 12kcal/kg for morbidly obese women (Table 3).^48-50 The overall carbohydrate content of this diet is 40% of total calories, with fat contributing 40% and protein 20%. When compared with the recommended ADA diet, the "euglycaemic diet" has less carbohydrate and more fat.

Table 3. Comparison of ADA supported and ‘euglycaemic’ diets for use by women with GDM.61

Recommendations regarding distribution of calories vary. Most programmes recommend 3 meals and 3 snacks. Carbohydrate intake at breakfast should be limited to approximately 10% of total calories. The remaining calories should be distributed as follows: 30% at both lunch and dinner, with the leftover calories distributed, as needed, as snacks. Insulin resistance is greatest in the morning, because pregnancy potentiates the naturally occurring hypercortisolaemia in the early morning hours.⁵¹

Programmes of moderate physical exercise have been shown to lower maternal glucose concentrations in women with GDM.² An area of controversy in the literature is whether or not exercise causes uterine activity. Durak et al recruited healthy pregnant women in their third trimester of pregnancy to exercise on 5 types of equipment while being monitored for maternal blood pressure, foetal heart rate and uterine activity.⁵² The researchers found that uterine activity correlated with the type of exercise, but not with the level of exertion. At equivalent workloads, the bicycle ergometer led to uterine activity in 50% of sessions, the treadmill in 40%, the rowing ergometer in 10%, recumbent bicycle in 0%, and the upper arm ergometer in 0%. Therefore, the upper body ergometer and the recumbent bicycle appear to be the safest forms of aerobic exercise studied.

In a follow-up study, Jovanovic et al randomised 20 women with GDM into 2 groups.⁵³ One group received 6 weeks of intensive dietary therapy. The other group received 6 weeks of the same dietary therapy, but also exercised 3 times a week, 20 minutes per time, using an arm ergometer. The 2 groups’ glycaemic levels started to diverge by week 4 of the programme. By week 6, the women in the exercise group had normalised their glycosylated haemoglobin levels, fasting plasma glucose levels and 1-hour postprandial plasma glucose levels on a 50g oral GCT. Although glycaemic control improved, the diet control group still had elevated fasting plasma glucose levels and postprandial hyperglycaemia. The researchers concluded that arm ergometer training is feasible and might provide a useful treatment option for women with GDM.

Women with GDM can be taught to do arm exercises at home while sitting comfortably in a chair with good back support and lifting weights while watching television for at least 20 minutes per session. They should avoid exercise in the supine position because it is associated with decreased cardiac output from pressure of the gravid uterus on the vena cava.

Insulin is the pharmacologic therapy that has most consistently been shown to reduce foetal morbidities when added to medical nutrition therapy.^43,45,54-56 Approximately 15% of women with GDM require insulin therapy because of elevated blood glucose concentrations despite dietary therapy.

Selection of pregnancies for insulin therapy can be based on measures of maternal glycaemia with or without assessment of foetal growth characteristics.²

The ADA recommends insulin when MNT fails to maintain self-monitored glucose at the following levels:²

Fasting plasma glucose £ 5.8mmol/l or

1-h postprandial plasma glucose £ 8.6mmol/l or

2-h postprandial plasma glucose £ 7.2mmol/l

Simple foetal measurements made by ultrasound can also be utilised to guide insulin therapy.

In a study by Buchanan et al, foetal ultrasound were done early in the third trimester for 303 consecutive women with GDM and a fasting serum glucose level < 5.8mmol/l on diet therapy.⁵⁷ Ninety-eight women had a foetal abdominal circumference (AC) ³ 75th percentile for gestational age, and 59 women completed a randomised trial of diet therapy or diet plus twice-daily insulin. The result showed that birth weights and the prevalence of large-for-gestational age infants were reduced in the insulin-treated group. These infants were at high risk of foetal macrosomia in the absence of standard glycaemic criteria for insulin therapy.

Unlike approaches that rely solely on frequent measures of each patient’s glucose levels, the ultrasound-guided approach can reduce the number of women who require self-monitoring of glucose and/or exogenous insulin therapy, thereby providing the potential to improve cost-effectiveness of antepartum management of GDM.⁵⁸ Kjos et al showed that, in women with GDM and fasting hyperglycaemia, glucose plus foetal AC measurements identified pregnancies at low risk for macrosomia and resulted in the avoidance of insulin therapy in 38% of patients without increasing rates of neonatal morbidity.⁵⁹

With regard to concerns over repeated prenatal ultrasound examinations, Newnham et al showed that exposure to multiple prenatal ultrasound examinations from 18 weeks’ gestation onwards might be associated with a small effect on foetal growth but was followed in childhood by growth and measures of developmental outcome similar to those in children who had received a single prenatal scan.⁶⁰

No ideal insulin dosage or regimen has been identified for the management of GDM. The dose and type of insulin used is dependent upon the specific abnormality of blood glucose noted during monitoring.

If the fasting glucose level is > 5mmol/l, then intermediate-acting insulin should be given before bed, beginning with doses of 0.2U/kg/day. If the postprandial glucose level is elevated, pre-meal short-acting insulin should be prescribed, beginning with a dose of 1U per 10g of carbohydrates in the meal.⁶¹

If both fasting and postprandial glucose levels are elevated, or if a woman’s postprandial glucose levels can only be blunted if starvation ketosis occurs, a twice daily or a 4-injections-per-day regimen should be prescribed. Insulin is administered to provide the basal and the meal-related insulin bolus.

The most widely used regimen for patients with pregestational or gestational diabetes is insulin twice daily, the morning dose containing two-thirds of the total daily insulin and the afternoon dose containing one-third of the total daily insulin.⁶² The morning dose comprises one-third short acting insulin and two-thirds intermediate-acting insulin whereas the afternoon dose comprises equal amounts of short-acting and intermediate-acting insulin. The disadvantages of this regimen are hyperglycaemia after lunch and possible nocturnal hypoglycaemia.

An alternative regimen requires 4 injections a day (Table 4). This regimen involves the use of preprandial short-acting insulin to control postprandial glucose values with the addition of bedtime intermediate-acting insulin if fasting glucose levels rise. In one study, Nachum et al showed that giving insulin 4 times rather than twice daily in pregnancy improved glycaemic control and perinatal outcome without further risking the mother.⁶³

Table 4. Initial calculation of insulin therapy for a regimen requiring four injections per day for GDM.

It is possible to decrease the number of injections to 3 per day if the patient is willing to coincide her lunch with the pre-programmed insulin midday peak if morning intermediate-acting insulin is increased. Pre-lunch insulin would therefore not be necessary.⁶¹

Insulin resistance increases as gestation proceeds, requiring an increase in insulin dose. Insulin doses should be calculated and range from 0.7U/kg body weight for weeks 6 to 18, to 0.8U/kg for weeks 18 to 26, to 0.9U/kg for weeks 26 to 36, and to 1.0U/kg for weeks 36 to term.

The ideal insulin regimen for the management of GDM would eliminate the typical acute postprandial hyperglycaemia and also prevent fasting hyperglycaemia and nocturnal hypoglycaemia.

Insulin lispro, an analogue of human insulin, possesses unique properties that facilitate lowering the postprandial glucose concentration. The rapid absorption of insulin lispro allows for a faster peak insulin concentration versus regular human insulin. This effect more closely mimics the physiological first-phase insulin release and results in lower postprandial glucose concentrations.

So far, a limited number of studies have been conducted using insulin lispro in pregnancy.

Jovanovic et al compared the metabolic effects of insulin lispro and regular human insulin and showed that those receiving insulin lispro had fewer hypoglycaemic episodes before breakfast but no difference in the mean fasting glucose and end point HbA1c.⁶⁴ In addition, anti-insulin antibody levels were similar in the 2 groups and insulin lispro was not detectable in the cord blood.

Persson et al randomised 33 pregnant women with type 1 diabetes mellitus to treatment with insulin lispro or regular insulin.⁶⁵ The study showed no difference in the HbA1c values between the 2 groups, suggesting that it is possible to achieve at least as adequate glycaemic control with insulin lispro as with regular insulin therapy in type 1 diabetic pregnancies. Masson et al showed that the use of insulin lispro in type 1 diabetes during pregnancy results in outcomes comparable to other large studies of diabetic pregnancy.⁶⁶

Data regarding the potential safety of insulin analogues in pregnancy are limited. Scherbaum et al conducted a retrospective study of women receiving insulin lispro or regular human insulin during pregnancy.⁶⁷ This study showed no difference in the rate of foetal structural malformations.

One of the widely debated issues is the possible deleterious effect of insulin lispro on maternal progression of diabetic retinopathy. Loukovaara et al compared the effect of insulin lispro versus regular human insulin on the progression of retinopathy during pregnancy in type 1 diabetic women.⁶⁸ It was found that insulin lispro improved glycaemic control with no adverse impact on progression of diabetic retinopathy.

Another insulin analogue that is likely to play a growing role in diabetic pregnancy will be insulin aspart. Pettitt et al recruited 15 women with GDM who had inadequate diabetes control with diet and exercise, and were therefore candidates for insulin therapy.⁶⁹ Breakfast meal tests were performed on 3 consecutive days — the first with no exogenous insulin and the other 2 after the injection of either regular insulin or insulin aspart. This study showed that effective postprandial glycaemic control was brought about by insulin aspart through higher insulin peak and lower demand on endogenous insulin secretion. Regular human insulin failed to make a significant impact in lowering the postprandial glucose concentration.

Insulin glargine is currently not licensed for use in pregnancy. No systemic investigations into the use of insulin glargine during pregnancy in humans have been reported to date. The only data comes from animal studies. Maternal and embryo-foetal toxicity was observed in rabbits treated with insulin glargine and the effects were related to the hypoglycaemic action of insulin.⁷⁰

Two case reports have been published. Devlin et al reported the first use of insulin glargine in a pregnant woman with type 1 diabetes.⁷¹ The treatment was initiated after finalised embryogenesis in the 14th week of pregnancy as the patient was suffering from recurrent nocturnal hypoglycaemic episodes. Holstein et al reported the case of a pregnant patient with type 1 diabetes, who received insulin glargine during the entire embryogenesis period.⁷² In both cases, the postpartum period was uneventful except for transient neonatal hypoglycaemia.

When insulin is needed in the management of GDM, the ADA recommends human insulin, noting "the use of insulin analogues has not been adequately tested in GDM".² The ACOG acknowledges that insulin lispro "may be helpful in improving postprandial glucose concentrations".³²

Oral hypoglycaemic agents have generally not been recommended during pregnancy. The ADA and ACOG do not endorse the use of oral hypoglycaemic agents.

Sulphonylurea drug therapy has been considered to be contraindicated in women with GDM because of the drugs’ ability to cause foetal hyperinsulinaemia and therefore macrosomia and prolonged neonatal hypoglycaemia. Zucker et al showed that the use of chlorpropamide during pregnancy was associated with prolonged symptomatic neonatal hypoglycaemia.⁷³

There was also concern about the possibility of congenital malformations. Piacquadio et al reported a potential teratogenic risk for first trimester chlorpropamide use.⁷⁴ Out of 20 women who received oral hypoglycaemic agents during early pregnancy, half had babies with birth defects.

Unlike first generation sulphonylurea agents which readily cross the placenta, the demonstration that glibenclamide (glyburide) minimally crosses the human placental barrier paved the way for an evaluation of glibenclamide as a treatment for GDM.^75,76

Three reports have suggested that glibenclamide may be a safe and effective treatment of GDM.^77-79 In a randomised, controlled trial comparing glibenclamide with traditional insulin therapy in 404 women with GDM, Langer et al showed that adequate glycaemic control was obtained with significantly less hypoglycaemia in the glibenclamide group than in the insulin group.⁷⁸ There were no differences in the frequency of macrosomia, neonatal hypoglycaemia, congenital anomalies and other neonatal morbidity. The cord-serum insulin concentrations were similar in the two groups, and glibenclamide was not detected in the cord serum of any infant in the glibenclamide group. In another study, Kremer et al showed that approximately 80% of patients with GDM who failed to respond to diet therapy could be effectively treated with glibenclamide.⁷⁹

Although metformin is expected to cross the placenta based on its relatively small molecular weight, the fact that it does not stimulate insulin secretion makes it a potentially attractive drug from the foetal perspective.⁷⁵ Given that pregnancy is a state of insulin resistance, metformin might be a logical alternative.

Women with GDM have been treated with metformin, predominantly in those with polycystic ovary syndrome.^80-86 A study by Glueck et al showed that in women with polycystic ovary syndrome who conceived while taking metformin, continuation of treatment through pregnancy reduced the incidence of gestational diabetes.⁸⁴

A retrospective study by Hellmuth et al reported an increase in perinatal losses and preeclampsia in a small cohort of metformin-treated women compared with women taking insulin or a sulphonylurea.⁸² However, the groups were not matched, with the metformin group mostly being treated in the third trimester and having increased risk factors for preeclampsia.

A prospective, randomised controlled trial is currently underway, comparing metformin with insulin in women with GDM (the Metformin in Gestational Diabetes [MiG] study).⁸⁷

A Mexican study of six women with GDM treated with acarbose before each meal demonstrated a normalization of fasting and postprandial serum glucose levels. These women experienced persistent intestinal discomfort while taking acarbose.⁸⁸

No published human reproductive studies regarding the use of other oral hypoglycaemic agents, including thiazolidinediones (rosiglitazone or pioglitazone) and non-sulphonylurea secretogogues (repaglinide or nateglinide) have been identified.

Most women with GDM are normoglycaemic after delivery. However, they are at risk for recurrent GDM, impaired glucose tolerance (IGT), and overt diabetes.

It is estimated that GDM recurs in 30 to 69% of subsequent pregnancies after a pregnancy with GDM.^89-94 One of the major risk factors for developing GDM is having had a previous pregnancy complicated by the disease. In a large population-based cohort of women who had GDM during in initial pregnancy, MacNeill et al showed that infant birth weight in the index pregnancy and maternal prepregnancy weight before the subsequent pregnancy were predictive of recurrent GDM.⁹⁵ In another study by Moses et al, those women who had a recurrence of their GDM were older, more parous, and had an increase in weight between the pregnancies.⁹³

Kim et al conducted a systematic literature review to examine factors associated with variation in the risk for type 2 diabetes in women with prior GDM.⁹⁶ This review showed that after the index pregnancy, the cumulative incidence of diabetes ranged from 2.6% to over 70% in studies that examined women 6 weeks to 28 years postpartum. After adjustment for various lengths of follow-up and testing rates, the cumulative incidence of type 2 diabetes increased markedly in the first 5 years after delivery and appeared to plateau after 10 years. An elevated fasting glucose level during pregnancy was the risk factor most commonly associated with the future risk of type 2 diabetes.

According to the ADA guideline, reclassification of maternal glycaemic status should be performed at least 6 weeks after delivery.² If glucose levels are normal postpartum, reassessment of glycaemia should be undertaken at a minimum of 3-year intervals. Women with impaired fasting glycaemia (IFG) or IGT in the postpartum period should be tested for diabetes annually.

Early interventional measures to halt the progression to diabetes should be implemented in those with IFG or IGT and in those women at high risk for type 2 diabetes. Buchanan et al recruited 266 Hispanic women with previous GDM and randomised them to placebo or the insulin-sensitising drug troglitazone administered in double-blind fashion.⁹⁷ During a median follow-up of 30 months, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone respectively (P < 0.01). The protective effect was associated with the preservation of pancreatic b -cell function and appeared to be mediated by a reduction in the secretory demands placed on b -cells by chronic insulin resistance.

However, the success of any early intervention programme would depend largely on postpartum follow-up. In a study by Tan et al, the non-respondent rate to postpartum diabetes screening was 37.1%.⁹⁸ The non-responders were found to be significantly heavier, with more severe hyperglycaemia during their pregnancy and had bigger babies compared to the responders with normal postpartum OGTT. These features resembled those who had failed their postpartum OGTT.

As such, a more effective call and recall system and education programme is needed to ensure postpartum attendance of all patients with GDM.

Previous study has shown a significantly higher prevalence of diabetes in offspring of women with diabetes during pregnancy than in offspring of non-diabetic and prediabetic women.⁹⁹ Intrauterine exposure to diabetes is also associated with a higher prevalence of IGT and obesity in adolescence.^100,101 However, the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, Dabalea et al compared the prevalence of diabetes and the mean BMI in siblings born before and after their mother was recognised as having diabetes.¹⁰² Consequently, siblings born before and after differed in their exposure to diabetes in utero. It was found that the risk of diabetes were significantly higher in siblings born after the mother developed diabetes than in those born before the mother’s diagnosis of diabetes. The mean BMI was also higher in offspring of diabetic than in offspring of non-diabetic pregnancies. In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes.

Another study by Sobngwi et al showed that exposure to a diabetic environment in utero is associated with increased occurrence of IGT and a defective insulin secretory response in adult offspring, independent of genetic predisposition to type 2 diabetes.¹⁰³ This insulin secretory defect could be related to low parasympathetic tone.

Major congenital malformations remain the leading cause of mortality and serious morbidity in infants of mothers with type 1 and type 2 diabetes.¹⁰⁴ In a cohort study by Casson et al, infants of women with pre-existent insulin dependent diabetes mellitus had a 10-fold risk of a congenital malformation and a 5-fold risk of being stillborn than infants in the general population.¹⁰⁵

Studies have demonstrated reductions in rates of malformations in the infants of type 1 diabetic women who had participated in preconception care to achieve stringent blood glucose control in the preconception period and during the first trimester of pregnancy.^106,107 However, unplanned pregnancies occur in about two-thirds of women with diabetes.¹⁰⁴

The general goal for glycaemic management in the preconception period and during the first trimester should be to obtain the lowest HbA1c level possible without undue risk of hypoglycaemia in the mother. This can be accomplished by a multidisciplinary team (diabetologist, obstetrician, diabetic nurse educator, dietician and other specialists), with the diabetic woman becoming the most active member of the team.

With an increasing prevalence of type 2 diabetes in younger populations, type 2 diabetes in pregnancy is certain to become a prominent concern.

The care of women with GDM has evolved over the past decades with better understanding of the pathophysiology of this condition. But the potential significance of the condition, as well as the criteria for screening and diagnosis, remain controversial. There is also controversy as to the value and method of blood glucose monitoring. Beyond the treatment foundation of medical nutrition therapy, exercise and standard insulin regimens, the treatment options for GDM has expanded, with both insulin lispro and glibenclamide comparing favourably to standard insulin regimens. Emphasis should also be placed in the recall and follow-up of this group of patients, as GDM is a pre-diabetic state. Further research is required so that we can replace some of the empiric recommendations with evidence-based guidelines.

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