Maternal diabetes in pregnancy: early and long-term outcomes on the offspring and the concept of "metabolic memory"

Abstract

The adverse outcomes on the offspring from maternal diabetes in pregnancy are substantially documented. In this paper, we report main knowledge on impacts of maternal diabetes on early and long-term health of the offspring, with specific comments on maternal obesity. The main adverse outcome on progenies from pregnancy complicated with maternal diabetes appears to be macrosomia, as it is commonly known that intrauterine exposure to hyperglycemia increases the risk and programs the offspring to develop diabetes and/or obesity at adulthood. This "fetal programming", due to intrauterine diabetic milieu, is termed as "metabolic memory". In gestational diabetes as well as in macrosomia, the complications include metabolic abnormalities, degraded antioxidant status, disrupted immune system and potential metabolic syndrome in adult offspring. Furthermore, there is evidence that maternal obesity may also increase the risk of obesity and diabetes in offspring. However, women with GDM possibly exhibit greater macrosomia than obese women. Obesity and diabetes in pregnancy have independent and additive effects on obstetric complications, and both require proper management. Management of gestational diabetes mellitus and maternal obesity is essential for maternal and offspring's good health. Increasing physical activity, preventing gestational weight gain, and having some qualitative nutritional habits may be beneficial during both the pregnancy and offspring's future life.

Figure 1

In GDM, adipose tissue secretes low adiponectin (anti-inflammatory and positive stimulator of insulin sensitizing) and high TNF-α and IL-6 which contribute to inflammatory state and insulin resistance in diabetic pregnancy as well as in macrosomia. Leptin, being pro-inflammatory, is highly produced by adipose tissue during diabetic pregnancy and insulin resistance (experimental study [75]) and implicated in the pathogenesis of weight gain in macrosomic babies. Leptin may exert its effects by interacting with neuropeptide-Y in the hypothalamus. The intrauterine hyperglycemia may act on the fetal hypothalamus and create a kind of “metabolic memory” which programs obesity and metabolic syndrome in the offspring during adulthood. (+) positive regulation (−) negative regulation. NPY, neuropeptide-Y.

Figure 2

Naïve CD4⁺ T-helper (Th0) cells can be differentiated into either Th1 cells, producing pro-inflammatory cytokines (IL-2, IL-12, IFN-γ) or Th2 cells, secreting anti-inflammatory cytokines (IL-4, IL-10, IL-5, IL-13). In normal pregnancy as well as in diabetic pregnancy, the Th1/Th2 balance shifts towards a protective Th2 phenotype, whereas it shifts towards a pro-inflammatory Th1 phenotype in macrosomia as well as in obesity. Moreover, reproductive hormone like hCG may contribute to the low Th1 phenotype in diabetic pregnancy associated with the successful pregnancy. Th, T helper cells; hCG, human chorionic gonadotrophin; GDM, gestational diabetes mellitus; (+) upregulation; (−) downregulation.