Maternal Diabetes Mellitus and Child Neurodevelopmental Disorders: Rethinking Causality in Light of Environmental...

Numerous epidemiological studies have linked maternal diabetes mellitus (DM) to neurodevelopmental disorders in offspring, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. However, recent evidence challenges a direct causal relationship: sibling-matched analyses show similar risks regardless of gestational DM status, and glycemic control during pregnancy does not consistently predict neurodevelopmental outcomes. We propose that exposure to environmental pollutants-rather than DM itself-may underlie these associations. Although usually examined separately, many pollutants both increase DM risk and disrupt fetal brain development, providing a biologically plausible basis for the observed epidemiological patterns. Because fetuses encounter these pollutants via placental transfer from maternal blood, understanding what determines maternal circulating pollutant levels is essential. Two major sources contribute: (1) ongoing external exposure through food, air, water, and consumer products, and (2) the release of previously accumulated lipophilic pollutants stored in adipose tissue. Often overlooked, adipose tissue serves as an important reservoir, and lipolysis mobilizes these compounds into circulation. Importantly, key pathophysiological features of DM-insulin resistance and insulin deficiency-accelerate lipolysis, increasing circulating pollutant levels. These pollutant-related mechanisms may also account for associations observed with other maternal conditions, such as obesity, eating disorders, psychological stress, and intrahepatic cholestasis of pregnancy, all of which may also be linked to elevated pollutant levels in maternal circulation. These insights suggest that maternal risk factors should be reconsidered in light of toxicokinetic dynamics, particularly the mobilization of lipophilic pollutants stored in fat. This perspective may offer a unifying explanation for otherwise disparate epidemiological findings and help guide more effective prevention strategies.