Pregravid Body Mass Index (BMI), Maternal Hypertriglyceridemia During Pregnancy and Body Composition/Metabolic Health of Asian GDM Offspring

The prevalence of gestational diabetes mellitus (GDM) worldwide is increasing, with accelerated rates of obesity in women of child-bearing age, increasing maternal age and improved survival of very low and high birth weight (BW) female offspring in modern times. GDM prevalence rates are known to be higher in some Asian populations compared with Western populations. The incidence rate amongst South Indians in India, and Malaysians in an urban tertiary centre in Kuala Lumpur are 14 and 11.4% respectively while in Western populations GDM only accounts for 2-9% of all pregnancies.

It is now well-established that exposure to an intrauterine diabetic milieu, in both pregnant women with type 2 diabetes (T2DM) and those with GDM, imparts increased future risk of diabetes, obesity, metabolic syndrome and cardiovascular disease in offspring. Besides maternal hyperglycemia, a strong link between maternal pregravid weight/maternal triglyceride (Tg) levels and fetal growth/childhood obesity/metabolic syndrome in offspring has been demonstrated in largely Caucasian populations.

The mechanisms of the developmental origins of adult disease however are poorly understood. The in utero environment via changes to the epigenome that do not involve alterations in DNA sequence can exert stimulatory or inhibitory effects on fetal growth and adiposity6. It has been proposed that a pathological metabolic milieu in utero results in fetal epigenetic changes such as DNA methylation and histone modification, thus modulating biological processes related to intrauterine development, such as gene expression, chromatin accessibility, DNA replication, imprinting and human disease patterns.

Lipotoxicity in adults is well-established to result in the development of insulin resistance and pancreatic beta-cell dysfunction. Much emphasis has already been given to management of maternal hyperglycemia during pregnancy. It is possible however that maternal hypertriglyceridemia on the other hand will soon become a therapeutic target in the fight against childhood diabetes and obesity. Normal pregnancy is associated with a physiological increase in Tg from 10 weeks gestation onwards; with a 2-3 fold increase in serum Tg levels by the 3rd trimester. These elevations can be attributed to enhanced hepatic production of VLDL, increased intestinal absorption of dietary lipids, reduced clearance of Tg due to decreased extra-hepatic lipoprotein lipase activity and reduced insulin sensitivity during pregnancy. Even so, Tg levels during pregnancy are known to be higher in women with T2DM and GDM when compared with healthy pregnant controls. Maternal hypertriglyceridemia independent of maternal glucose has been linked with increased BW and fetal adiposity in offspring of Caucasian women. This association has been shown to hold true in women with GDM as well as those with Normal Glucose Tolerance (NGT) but risk factors for GDM. Maternal hypertriglyceridemia has even been linked with pre-eclampsia. Indeed, the fact that Langer et al, has demonstrated that insulin therapy results in lower macrosomia rates in obese GDM women than diet therapy despite equivalent glycemic control seems to indicate that some other metabolic target besides glucose which is modulated by insulin therapy is in play. It is highly likely that this 'invisible' metabolic variable is maternal triglyceride.

Determining early predictors of development of metabolic syndrome (MS) in offspring will enable targeted childhood intervention programs. In Western populations it has been established that pregravid maternal BMI is a strong independent predictor of childhood obesity/MS whereas birth weight and GDM alone are poor correlates of offspring obesity and risk of metabolic syndrome. In Boney et al's cohort of Caucasian offspring who were evaluated from age 6, for example, combination of large for gestational age (LGA) status and maternal GDM was associated with OR of 10.4 of insulin resistance in offspring at age 11yrs and increased prevalence of MS at any age. However the prevalence of MS in offspring was not significantly different between offspring of mothers with NGT whether LGA/average for gestational age (AGA), and AGA offspring of GDM mothers. Neither were maternal GDM alone and LGA at birth independently associated with insulin resistance. Maternal obesity alone however independently conferred an approximate increase in hazard of MS of 2-fold by 11 years of age whereas GDM status alone did not. The risk of developing MS in GDM offspring diverged between those with LGA and AGA status at age 7, so that by the time these children were 11 years old the risk was 3.6 fold greater in LGA compared with AGA offspring of GDM mothers. Alarmingly 50% of GDM offspring who had LGA status at birth had at least 2 out of 4 criteria of MS at any age-point between the ages of 6-11 years. These associations and relationships however are less well-delineated in Asian populations. In addition, much of these data, including those of Boney et al's are based on diagnostic definitions of GDM that have altered since the evidence obtained from the HAPO study. It is possible that Malaysian GDM offspring may develop a higher risk of metabolic syndrome at an age younger than 7 years and therefore require intervention programs before the age of school attendance. Hence the need for studies evaluating metabolic health in GDM offspring in the local Malaysian setting based on current diagnostic criteria of GDM that will enable more effective intervention programs tailored to the local setting and based on local data. There is also evidence in Caucasian and Hong Kong Chinese offspring that in utero hyperinsulinemia is an independent predictor of abnormal glucose tolerance in childhood. In Hong Kong Chinese offspring, cord blood insulin was very predictive of abnormal glucose tolerance in children aged 8 years (OR 6.12) whereas BW > 4kg was not, indicating perhaps that in Asians as well, BW is a poor early predictor of risk of metabolic dysfunction. Evidence indicates that dyslipidemia precedes development of dysglycemia in offspring of GDM mothers but that there are subtle differences between Caucasians and Asians with regards to which component of the lipid profile is impaired. Studies have shown that hypertriglyceridemia is more prevalent than dysglycemia in Caucasian GDM offspring aged 7-11 years , whereas low HDL is more common in Hong Kong Chinese GDM offspring aged 8.