Prenatal maternal diabetes exposure linked with increased risk of psychiatric disorders: JAMA

Raquel Nogueira Avelar e Silva and team hypothesized that prenatal exposure to a maternal diabetes diagnosis during pregnancy would increase the risk of offspring developing psychiatric disorders in childhood and adulthood (up to the age of 40 years). In this Danish population-based cohort study, they investigated the associations between maternal diabetes diagnosed before or during pregnancy and the onset of 10 broad types of psychiatric disorders in offspring during the first 4 decades of life. Specifically, the risks of maternal diabetes during pregnancy associated with any psychiatric disorder, substance use disorders, schizophrenia, mood disorders, anxiety disorders, eating disorders, personality disorders, intellectual disorders, developmental disorders, and behavioral disorders.

The study investigated the associations between maternal diabetes diagnosed before or during pregnancy and 10 types of psychiatric disorders in offspring during the first 4 decades of life. This population-based cohort study used data from several Danish nationwide medical and administrative registries in Denmark on all 24,13,335 live births from 1978 to 2016. Data were analyzed between October 1, 2019, and July 15, 2021. Any maternal diabetes diagnosis during pregnancy (56,206 offspring [2.3%]) and 3 diabetes subtypes (pregestational type 1 diabetes, 22,614 offspring [1.0%]; pregestational type 2 diabetes, 6713 offspring [0.3%]; and gestational diabetes, 26,879 offspring [1.1%]).

Outcomes included 10 types of psychiatric disorders: any psychiatric disorder, substance use disorders, schizophrenia, mood disorders, anxiety disorders, eating disorders, personality disorders, intellectual disorders, developmental disorders, and behavioral disorders.

A total of 24,13,335 individuals were included in this study. During the 39-year follow-up time, 1,51,208 offspring (6.4%) received a diagnosis of a psychiatric disorder.

Offspring born to mothers with any diabetes diagnosis during pregnancy were at increased risk of developing any psychiatric disorder (HR, 1.15; 95% CI, 1.10-1.20), schizophrenia (HR, 1.55; 95% CI, 1.15-2.08), anxiety disorders (HR, 1.22; 95% CI, 1.09-1.36), intellectual disabilities (HR, 1.29; 95% CI, 1.11-1.50), developmental disorders (HR, 1.16; 95% CI, 1.03-1.30), and behavioral disorders (HR, 1.17; 95% CI, 1.08-1.27) compared with offspring born to mothers without a diabetes diagnosis during pregnancy. No association was observed for substance use disorders, mood disorders, eating disorders, and personality disorders.

The findings show that maternal diabetes during pregnancy was associated with increased risks for psychiatric disorders overall and several specific psychiatric disorders in a population-based Danish birth cohort. Study did not find associations of maternal diabetes during pregnancy with substance use disorders, mood disorders, eating disorders, and personality disorders in offspring.

GDM was associated with anxiety and intellectual disabilities only in combination with elevated maternal BMI. Increased maternal BMI during pregnancy may also be associated with psychiatric disorders via the inflammatory processes that occur in the uterus owing to the lipotoxic effects associated with overweight. Thus, although exposure to maternal diabetes during pregnancy is hypothesized to be associated with the neurodevelopment of offspring, the joint associations of maternal diabetes and an elevated BMI might engender more pronounced damages to neurodevelopment than the individual associations. Another possibility is that the environment may play a greater role than fetal programming for some psychiatric disorders.

The potential mechanisms underlying the observed associations between maternal diabetes during pregnancy and schizophrenia, anxiety disorders, intellectual disabilities, developmental and behavioral disorders may include oxidative stress and fetal hypoxia. The key mechanism may be associated with a chain of chemical reactions triggered by hyperglycemia that leads to increased production of reactive oxygen species (ROS), which are molecules containing oxygen derived from normal cell metabolism. As hyperglycemia increases and the ROS level increases, antioxidants in the body may be insufficient to counteract all ROS. In excessive amounts, ROS react with tissue molecules, leading to oxidative stress. In embryos, oxidative stress can damage the DNA of all types of cells, including the central nervous system. This damage may lead to long-lasting neurodevelopmental impairments, including psychiatric disorders.

"Our study shows a pattern in which prenatal exposure to maternal diabetes diagnosed during pregnancy was associated with increased risks for several psychiatric disorders in the first 4 decades of life. Children born to mothers with any diabetes diagnosis during pregnancy had increased risks of any psychiatric disorder, schizophrenia, anxiety disorders, intellectual disabilities, developmental disorders, and behavioral disorders. These findings suggest that careful clinical management of maternal diabetes during pregnancy is needed. Overall, our findings signal the importance of effective strategies for preventing, screening, and treating diabetes among women of fertile age for women's health and children's mental health."

doi:10.1001/jamanetworkopen.2021.28005