Diagnosing hyperglycemia (GDM) in pregnancy: closing the door after the horse has bolted?

IntroductionA common belief is that gestational hyperglycemia ( GDM) develops during pregnancy and remits after delivery. It increases the risk of diabetes and obesity in the offspring and fuels the intergenerational epidemic of diabesity in the young. Intensive glycemic treatment in pregnancy RCTs failed to prevent this transmission because the critical pre- and peri-conceptional window for epigenetic programming was missed. Some studies have reported that women diagnosed with GDM were already hyperglycemic, obese, and insulin resistant before pregnancy. However, little is known about the life-course evolution of glycemia before the diagnosis of pregnancy hyperglycemia. The Pune Maternal Nutrition Study (PMNS) birth cohort has measured plasma glucose serially throughout childhood, puberty, young adulthood, pregnancy, and later, providing a unique opportunity to test the hypothesis that pregnancy hyperglycemia is only a window in lifetime hyperglycemia. MethodsThe PMNS birth cohort, established in 1993, included serial glucose measurements at ages 6, 12, and 18 years, as well as for females during pregnancy and post-delivery follow-up. Of 366 female cohort members, 171 became pregnant and delivered by February 2020. Given the small number of GDM (IADPSG criteria) we defined pregnancy hyperglycemia as the upper quartile (Q4) of fasting plasma glucose (FPG) and area under the curve (AUC) during an OGTT at 28 weeks gestation. ResultsAt 28wks gestation these women were young (mean age 20.9y) and had a median BMI 21.7 kg/m2 [IQR, 20.0, 23.8]; 44 women had fasting hyperglycemia (FPG >4.7 mmol/l) and 39 had AUC hyperglycemia (AUC > 8.57 x 102). For both groups, hyperglycemic women had higher glycemia from childhood through post-delivery compared to normoglycemic women, and higher HbA1c before pregnancy. Having an FPG above the highest quartile from childhood increased the odds of pregnancy hyperglycemia 2.22 times (95% CI 1.45, 3.38), and post-delivery glucose intolerance 5.22 times (2.40, 11.33); for AUC, the odds were 2.88 (1.31, 6.28) and 3.50 (1.36, 8.97) respectively. InterpretationPregnancy hyperglycemia reflects persistent hyperglycemia since childhood. Diagnosing and managing hyperglycemia ( GDM) in pregnancy does not prevent exposure of the ovum and early embryo to an abnormal metabolic milieu and will not curtail the escalating epidemic of diabesity in the offspring. A pre-conceptional primordial approach is essential. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSO_LIMost clinicians and researchers believe that gestational diabetes develops during pregnancy and remits after delivery C_LIO_LISome studies have reported higher glucose, HbA1c, lipids, and BMI years before diagnosis of GDM but these are underplayed as risk factors C_LIO_LIRandomised controlled trials of intensive glycemic control in pregnancy (usually initiated in the third trimester) do not prevent the long-term risk of diabetes and obesity in the offspring C_LIO_LIThis may be partly due to genetic transmission but more likely due to pre- and peri-conceptional epigenetic programming due to maternal metabolic status C_LI Whats new in this studyO_LIWe describe for the first time a life course trajectory of glycemia and body size in women with pregnancy hyperglycemia, in the Pune Maternal Nutrition Study, a preconceptional birth cohort initiated 30 years ago C_LIO_LIWomen with pregnancy hyperglycemia had consistently elevated glycemia from childhood, puberty, and young adulthood through pregnancy and post-pregnancy C_LIO_LIThis demonstrates that pregnancy hyperglycemia is only a window in the life course hyperglycemia and not a de novo phenomenon. C_LI Implications of all the available evidenceO_LIOur findings suggest that primordial prevention of the intergenerational vicious cycle of diabetes and obesity may be achieved by management of metabolic abnormalities before pregnancy C_LIO_LIThis will shift the focus from the clinic to the community, from clinical medicine to public health C_LIO_LIFurther research will define the role of genetic and epigenetic factors involved C_LI