GDM and the worldwide pandemic of obesity, metabolic syndrome and type 2 diabetes

The increase in the prevalence of type 2 diabetes (T2D) is creating a non-communicable disease global health crisis. The worldwide prevalence of diabetes in 2000 was estimated to be 2.8%, with an expected rise to 4.4% by 2030, equating to 366 million persons with diabetes in 2030. The greatest rises in prevalence are predicted to occur in India, China, Latin America and the Middle East. This increase in T2D is inextricably linked to the rise in obesity prevalence. The incidence of GDM is also rising, paralleling the rises in T2D and obesity prevalence. This is not surprising, considering that GDM and T2D share the same underlying pathogenic mechanisms. They are essentially different phases of the same disease for the mothers. The incidence, however, is difficult to compare from country to country because of differences in screening and diagnosis practices. If the recently published International Association of Diabetes and Pregnancy (IADPSG) recommendations on the diagnosis and classification of hyperglycaemia in pregnancy are adopted, the incidence is expected to be approximately 16–18% of pregnancies. Importantly, GDM incidence is likely to have predictive value for future trends in T2D prevalence. Furthermore, GDM also provides an opportunity for timely intervention in mothers and their families to assist in turning this pandemic of metabolic disease around.

What is the significance of GDM for the woman and her baby during pregnancy?

The HAPO study confirmed in over 23 000 women from 15 countries that hyperglycaemia in pregnancy, at levels less than that of diabetes and unknown to the woman or her carers, and adjusted for potential confounders, increases the risk of large-for-gestational age (LGA)/macrosomic babies, neonatal hyperinsulinism at birth as reflected by elevated cord C-peptide, neonatal hypoglycaemia, excess neonatal adiposity, shoulder dystocia or birth injury, neonatal hyperbilirubinaemia, primary caesarean section and pre-eclampsia. The strong associations between maternal hyperglycaemia, cord blood C-peptide, birth weight and neonatal adiposity are highly consistent with the Pedersen hypothesis. Pedersen postulated that maternal hyperglycaemia, by increasing glucose passage across the placenta, promotes foetal hyperinsulinism and, this in turn, causes diabetic foetopathy, including increased foetal adiposity and neonatal hypoglycaemia. HAPO did not show that hyperglycaemia, less than that of overt diabetes, is associated with an increased risk of perinatal mortality.

ACHOIS and the MFMUN-GDM clinical trials have demonstrated that diagnosis and treatment of GDM are worthwhile, as this does reduce the risk of many of the adverse pregnancy outcomes of GDM without causing harm. In both studies, women who had been diagnosed with GDM late in the 2nd–early 3rd trimesters were randomised to either routine care (women and carers were blinded to GDM diagnosis) or intervention. Intervention in both trials consisted of dietary advice, blood glucose monitoring and insulin therapy, as needed. In the ACHOIS study, a composite measure of serious perinatal complications (defined as one or more of death, shoulder dystocia, bone fracture and nerve palsy) was reduced by diagnosis and intervention (adjusted odds ratio (AOR) 0.33, 95% confidence interval (CI) 0.14–0.75, p = 0.01). A similar composite measure in the MFMUN-GDM study was reduced, but this was not statistically significant (relative risk 0.87, 97% CI 0.72–1.07, p = 0.14). In both studies, rates of LGA/macrosomia and pre-eclampsia were reduced by intervention. Intervention also reduced maternal pregnancy weight gain in both studies. Shoulder dystocia and caesarean section were significantly reduced by treatment in the MFMUN-GDM trial only. Induction of labour rates and admission to the special care nursery were increased by treatment in the ACHOIS trial only. Overall, these two trials show that diagnosis and management of GDM with what is a very standard approach can improve pregnancy outcome.

Of particular note, the traditional definition of GDM “glucose intolerance with onset or first recognition in pregnancy” includes women with unknown pre-existing diabetes, particularly T2D. The outcomes of T2D in pregnancy are at least as bad, and may even be worse, than those of type 1 diabetes (T1D). These adverse outcomes include increased rates of congenital malformation and perinatal death. With the rapidly increasing prevalence of T2D in women of childbearing age, undiagnosed T2D in pregnancy is much more common. For this reason, it is time to review the generally accepted definition of GDM and categorise pre-existing overt diabetes recognised for the first time in pregnancy as such rather than GDM. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel, in its recent statement on the diagnosis and classification of hyperglycaemic disorders in pregnancy recognised this as a major issue. The panel suggested that a screen for overt diabetes be performed at the first antenatal visit. However, to reliably prevent congenital malformations in these pregnancies, efforts to diagnose women with overt diabetes prepregnancy need to be pursued.

GDM and lifelong health of the mother

Women with GDM are very often on a pathway to the development of T2D. As discussed below, GDM uncovers an inability of the islet β-cell to compensate for the insulin resistance of pregnancy. Islet β-cell failure to compensate for insulin resistance underlies the pathophysiology of T2D. In an Australian study of 5470 GDM patients and 783 control subjects, the risk of developing diabetes was 9.6 times greater for patients with GDM. The cumulative risk of T2D for the GDM patients was 25.8% at 15 years post diagnosis. In a systematic review, the cumulative incidence of T2D following GDM pregnancy in 28 studies ranged from 2.6% to 70%, with factors such as duration of follow-up (6 weeks up to 28 years), diagnostic criteria for GDM used and the rate of retention of subjects in follow-up differing considerably across studies.

GDM is also a risk factor for cardiovascular disease (CVD) events. In a large population based study in Ontario, Canada, women who had GDM in pregnancy ( n = 8191) compared with a matched control group ( n = 81 262) were at higher risk of CVD events with a hazard ratio of 1.71 (95% CI 1.08–2.69). When adjusted for the subsequent development of T2D, this ratio was no longer significant such that a considerable part of the post-GDM increased CVD risk was attributable to progression to T2D. Therefore, a diagnosis of GDM for each woman provides an opportunity for intervention to reduce her risk of future T2D and CVD.

GDM and lifelong health of the baby

There is very strong epidemiological and experimental evidence linking intrauterine growth restriction (IUGR) with later adult diseases such as obesity, hypertension, T2D and CVD. ‘Foetal origins of adult disease’ is on the agenda of many health-related conferences. Therefore, is there evidence showing that the intrauterine environment of GDM can contribute to adult disease? There is evidence from animal studies, but human data is more limited.

In longitudinal studies of the Pima Indians from Arizona, a population that has an extremely high prevalence of obesity and T2D, established diabetes in mothers during pregnancy does increase the incidence of diabetes in the offspring, particular at young age. An association was found between maternal diabetes in utero and age at offspring’s diagnosis of T2D in the multiethnic SEARCH for diabetes in youth study. Both lines of evidence support the concept that exposure to hyperglycaemia in utero increases the subsequent risk of diabetes in the offspring. The mild hyperglycaemia of GDM, however, was not considered in these studies.

In a predominantly Caucasian population in Denmark, the offspring of women with diet-treated GDM and women with T1D were followed up. At 22 years of age, 21%, 11% and 4% of the offspring of GDM, T1D and control women, respectively, had T2D or pre-diabetes. The AORs for T2D/pre-diabetes were 7.8 (95% CI 2.6–23.4) and 4.0 (95% CI 1.31–12.3) for the offspring of GDM and T1D women, respectively, compared with the offspring of control women. The AORs for metabolic syndrome were 4.1 (95% CI 1.7–10.0) and 2.6 (95% CI 1.0–6.5) for the offspring of diet-treated GDM and T1D. Clearly, offspring of women with GDM are at a significantly higher risk of overweight and T2D. A prevalence of 21% of T2D/pre-diabetes at the age of 22 years is very high and concerning. While it is difficult to determine the relative contributions of the intrauterine environment compared with genes and the post-pregnancy environment on these findings in the children of GDM women, the same trends in the children of T1D women strongly indicate the hyperglycaemia of the intrauterine environment as being important. This conclusion is reinforced by the finding of an association between maternal glucose control late in pregnancy and the risk of T2D/pre-diabetes in the offspring of the T1D mothers.

Of concern in the Danish study, the children of the women with diet-treated GDM did not do well in follow-up with respect to the development of overweight and hyperglycaemia. The questions remain: Can optimal management of GDM during pregnancy reduce the risk of metabolic syndrome and diabetes in the offspring later in life? If so, what is the optimal management protocol? Can we do more after pregnancy (e.g., during the neonatal period and early childhood) to reduce the long-term risk for the offspring?

GDM is a condition of failure of the islet β-cell to compensate for insulin resistance

For the majority, the occurrence of GDM is an indication of an underlying risk for T2D. A small percentage of women with GDM, however, will have early T1D or maturity onset diabetes of the young (MODY). It is important to be aware of these possibilities, if women with GDM have atypical presentations. For example, early T1D needs to be considered in lean women with relatively high blood sugar levels. MODY needs to be considered in non-obese pregnant women with strong family histories of early-onset non-insulin-requiring diabetes. The following discussion of pathophysiology, however, concerns the majority of GDM women at risk of T2D.

The hyperglycaemia in women with GDM develops due to a failure of islet β-cells to sustain compensatory insulin secretion for insulin resistance. Many of the women destined to develop diabetes will have had insulin-resistance prepregnancy usually related to overweight and obesity. Maternal adaptation to pregnancy also includes a physiological induction of insulin resistance that will aggravate any pre-existing insulin resistance. Thus, pregnancy-induced aggravation of insulin resistance exerts a major load on islet β-cells, and women with an underlying susceptibility to islet β-cell failure will develop GDM.

Considering that islet β-cell failure to insulin resistance is a necessary factor in the pathogenesis of T2D, it is no surprise that GDM predicts it so well. Pregnancy-induced insulin resistance can, therefore, be considered to be an islet β-cell stress test for the prediction of T2D risk.

What is the relative contribution of obesity and hyperglycaemia to adverse pregnancy outcomes in GDM pregnancy?

The HAPO study showed that even mild degrees of hyperglycaemia, after adjustment for confounding factors including maternal body mass index (BMI), are associated with greater risk of LGA babies, clinical neonatal hypoglycaemia and raised cord blood C-peptide. From the same study, higher maternal BMI, independent of maternal hyperglycaemia, was also strongly associated with excess foetal growth and adiposity, and increased pre-eclampsia. Thus, hyperglycaemia and high BMI are independent risk factors for adverse pregnancy outcome.

In a recent large Australian study, the AORs of being obese or morbidly obese for hypertensive disorders of pregnancy were 3.0 and 4.9; for GDM, 3.0 and 7.4; for hospital stay greater than 5 days, 1.5 and 3.2; and for caesarean section, 2.0 and 2.3. For the neonates, AOR of maternal obesity or morbid obesity for birth defects were 1.6 and 3.4, and for hypoglycaemia 2.6 and 7.1.

With respect to birth defects, a prospective cohort study (22 951 pregnancies) of early pregnancy exposures and pregnancy outcome in the UK showed that women who were both obese and diabetic were 3.1 times more likely to have a baby with a major congenital malformation compared with non-obese, non-diabetic women. Major congenital malformations, however, were not increased in pregnancies complicated by obesity alone or diabetes alone. It is highly likely, therefore, that obesity and diabetes synergise in causing adverse pregnancy outcomes.

Is excessive maternal weight gain a major confounding risk factor for adverse outcome in GDM pregnancy?

Excess weight gain in obese women, irrespective of glycaemic status, has been linked to adverse pregnancy outcome. Furthermore, higher maternal weight gain increases the risk of macrosomia in women with hyperglycaemia, such that the highest macrosomia rates are in women with the combination of gestational hyperglycaemia and excessive pregnancy weight gain. Thus, excessive weight gain is an additional risk factor for adverse outcomes in GDM pregnancy.

What is the relative importance of hyperglycaemia compared with the non-glycaemic components of the metabolic syndrome on pregnancy outcome?

The metabolic syndrome is a complex of interrelated risk factors for conditions such as non-alcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS) and cardiovascular disease as well as GDM and T2D. These risk factors include dysglycaemia, elevated triglyceride, low high-density lipoprotein (HDL)-cholesterol, raised blood pressure and central obesity. Other non-glycaemic factors associated with the metabolic syndrome include hyperinsulinaemia, elevated non-esterified fatty acids (NEFAs), hypoadipinectinaemia, a prothrombotic state and a pro-inflammatory state. Therefore, how important are the non-glycaemic factors and their interaction with elevated glucose?

Metabolic syndrome in early pregnancy has been shown to increase adverse pregnancy outcomes. For example, it increases the risk of pre-term birth. Altered adipocytokine levels measured early in pregnancy, known to occur in subjects with metabolic syndrome, are also associated with higher rates of pre-eclampsia. It also works the other way; pre-eclampsia and GDM are risk factors for post-partum metabolic syndrome.

What about lipids? Normal maternal metabolism during pregnancy is characterised by a physiological hyperlipidaemia. GDM, T2D and poorly controlled T1D, however, are often associated with even higher blood lipids than in normal pregnancy. Obese women have abnormal lipid profiles in pregnancy with a pattern of hypertriglyceridaemia, elevated very low density lipoprotein (VLDL)-cholesterol and low HDL-cholesterol, in association with hyperinsulinaemia, increased inflammatory markers and increased leptin. Women with higher range NEFA in the 3rd trimester are more likely to be overweight or obese. Elevated NEFA have been shown to be associated with pre-term delivery, IUGR, IUGR with pre-eclampsia and foetal adiposity. Whether elevated NEFA levels have a pathogenic role in these adverse events, or simply correlate with other metabolic syndrome pathogenic factors, however, is unknown.

Thus, the women we treat with GDM often have additional risk factors (confounders) for adverse pregnancy outcome. These include maternal obesity, dyslipidaemia, other metabolic syndrome-related factors and increased maternal age. These and other additional risk factors may act independently and/or synergistically to cause harm.

Does the GDM impact on short- and long-term health of the baby occur predominantly in the late 2nd and 3rd trimesters or does the impact start earlier?

The current paradigm used for the diagnosis and management of GDM is founded partly on O’Sullivan’s initial use of oral glucose tolerance tests (OGTTs) in middle to late pregnancy to predict diabetes after pregnancy and on Freinkel’s fuel-mediated teratogenesis hypothesis in which he predicted that GDM causes harm to the baby only in the second half of pregnancy. However, relative mild hyperglycaemia and hyperlipidaemia are almost certainly present in many GDM women from an earlier stage of pregnancy, and obesity is definitely present in many from earlier on. The ACHOIS study and the MFMUN-GDM study do show that the use of this paradigm is effective in reducing adverse perinatal outcomes. However, is diagnosing GDM at 24–28 weeks and managing it in the later part of pregnancy adequate to prevent the long-term harmful effects on the offspring? We do not have the answer to this important question.