Diagnosing hyperglycemia (GDM) in pregnancy: closing the door after the horse has bolted?
Authors: Yajnik Chittaranjan S. , Bandyopadhyay Souvik , Bhat Dattatray S. , Wagh Rucha H. , Yajnik Pallavi C. , Ladkat Rasika , Coyaji Kurus , Osmond Clive , Fall Caroline H.D. 
Published: October 2024

Introduction

Gestational diabetes (GDM) increases risk of diabetes and obesity (diabesity) in the offspring. However, intensive treatment of GDM (generally diagnosed late in pregnancy) has failed to reduce these outcomes in RCTs. The vital window for programming of diabesity is pre- and peri-conceptional, and is influenced by maternal metabolism. Though it is known that metabolic-endocrine abnormalities of ‘GDM’ may be detectable before pregnancy, there is little data on the life course precursors of pregnancy hyperglycemia.

Methods

The Pune Maternal Nutrition Study birth cohort was set up in 1993-96. 171/366 females born in the study had married and delivered a baby by Feb 2020. We have serial glycemic and body size data for these women at age 6, 12 and 18y, in pregnancy, and post-delivery.

Results

At 28-wks gestation the mothers were 21y old, their median BMI 22 kg/m2, and twenty had GDM (IADPSG). Given the small number of GDM, we called the 4thquartile of FPG (≥4.7 mmol/l, N=44) ‘fasting hyperglycemic’ and compared the serial fasting plasma glucose (FPG) of these with the remaining 126 (‘normoglycemic’). Women with fasting hyperglycemia had higher FPG at 6, 12 and 18-years and post-delivery, and higher HbA1c before pregnancy. Women with fasting hyperglycemia were thin as a group, but they had higher BMI and waist circumference throughout compared to normoglycemic.

Interpretation

Pregnancy glycemia reflects glycemia throughout childhood and adolescence. DiagnosingGDMin pregnancy ignores exposure of the ovum and the embryo to an abnormal metabolic milieu and fails to influence the periconceptional programming of diabesity. Diagnosing and treating GDM in late pregnancy will not curtail the escalating epidemic of diabesity in the young.

Research in context

Evidence before this study

Most clinicians and researchers believe that ‘gestational’ diabetes comes during pregnancy and goes away after delivery. The current practice is to diagnose GDM by an OGTT between 24-28 weeks though some suggest earlier diagnosis (at booking visit), especially in those at higher risk. Several studies, either by design or access to previous opportunistic investigation have reported higher glucose, HbA1c, lipids, and BMI years before diagnosis of GDM. A few cohorts have also reported higher glucose and HbA1c before pregnancy in those subsequently diagnosed with GDM. These markers have mostly been classified as ‘risk factors’ for GDM, without considering the possibility that a disorder was already present before pregnancy. On the other hand, a few epidemiologists have asserted that GDM is pre-gestational but this has not been much acknowledged and has not influenced clinical practice.

Maternal hyperglycemia adversely influences pregnancy outcomes, and increases long-term risk of diabetes and obesity in the offspring (as well as in the mother). Randomised controlled trials of intensive glycemic control in pregnancy (usually initiated in the third trimester, sometimes earlier) prevent some of the short-term pregnancy outcomes but not the long-term risk of diabetes and obesity in the offspring. This may be due to genetic transmission but more likely due to pre- and peri-conceptional ‘epigenetic programming’. Programming is influenced by the metabolic milieu of the ova and the conceptus which includes maternal metabolites, nutrients etc. This crucial period is systematically missed in the current clinical management of GDM

Our literature search revealed no study which has reported the life-course evolution of pregnancy glycemia which will have a bearing on the pre- and periconceptional programming of diabetes in the offspring.

Added value of this study

We describe for the first time a life course trajectory of glycemia in women born in a rural preconceptional birth cohort in India 30 years ago, followed throughout childhood and adolescence, marriage and pregnancy and developed gestational fasting hyperglycemia. We start with their exposure to maternal glycemia during intrauterine life, and track their consistently elevated glycemic curve from childhood into puberty, young adulthood, pregnancy, and post-pregnancy compared to that of women with ‘normal’ pregnancy glycemia. This demonstrates that the hyperglycemic women’s ova and conceptus would be exposed to higher glucose concentrations and that hyperglycemia in pregnancy is only a window in the life course and not ade novophenomenon. The glycemic separation between the two groups was exaggerated during the post-delivery follow-up, pushing these women towards type 2 diabetes.

Implications of all the available evidence

We provide proof that gestational hyperglycemia (GDM) is not only ‘gestational’ but is a continuation of elevated glycemia from early life. This has implications not only for the diagnosis and treatment of ‘GDM’ to improve pregnancy outcomes but especially for the primordial prevention of the intergenerational programming of the diabetes epidemic. Our results suggest that hyperglycemia in young women should be diagnosed and controlled before pregnancy to curtail pre- and peri-conceptional programming of diabetes. This will shift the focus from the clinic to the community, from clinical medicine to public health. Further research will define the role of genetic and epigenetic factors involved.