Maternal Type 1 Diabetes and Risk of Autism in Offspring

Abstract

Maternal preexisting type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) diagnosed by 26 weeks' gestation have been associated with increased risk of autism spectrum disorder (ASD) in offspring. 1 However, little is known about ASD risk associated with maternal preexisting type 1 diabetes (T1D). We extend previous observations by examining the risk of ASD in offspring associated with maternal T1D, T2D, and GDM. Methods | This retrospective cohort study included singleton children born at 28 to 44 weeks' gestation in Kaiser Permanente Southern California (KPSC) hospitals from January 1, 1995, through December 31, 2012. Children were tracked through electronic health records from age 1 year until the first date of the following: clinical diagnosis of ASD, last date of continuous KPSC membership, death, or study end date (December 31, 2017). The KPSC institutional review board approved this study and provided waiver of participant consent. Methods to identify ASD, T2D, and GDM exposure were described previously. 1 GDM exposure was divided into diagnosis by or after 26 weeks' gestation based on a prior finding that risk of ASD was elevated for exposure to GDM by 26 weeks. 1 T1D was identified using the algorithm developed for electronic health records data 2 and confirmed by prescription of insulin during pregnancy. Potential confounders were

BMI growth trajectory from ages 2 to 6 years and its association with maternal obesity, diabetes during pregnancy, gestational weight gain, and breastfeeding

“…A total of 128 540 children had complete and valid data on the four maternal exposure variables and covariates including maternal age, race/ethnicity, household income, birthweight, and gender. The validity of data has been established in previous publications …”

“…The primary exposure variables were (a) maternal prepregnancy obesity or overweight, (b) excessive gestational weight gain (EGWG), (c) maternal diabetes during pregnancy, and (d) breastfeeding > 6 months. Previous studies have described the constructions of these exposure variables . Briefly, maternal prepregnancy BMI was calculated from the weight and height data closest to the last menstrual period (LMP) recorded in EMR and was classified as normal (BMI < 25 kg/m 2 ), overweight (25 ≤ BMI < 30 kg/m 2 ) or obese (BMI ≥ 30 kg/m 2 ).…”

“…Maternal diabetes was classified as pre‐existing T1D or T2D or GDM with or without receiving antidiabetic medication treatments or no diabetes during pregnancy. Pre‐existing T2D status was determined based on combinations of International Classification of Diseases codes, glucose and glycated haemoglobin A1c levels, as well as use of antidiabetic medications prior to pregnancy . T1D was identified according to Klompas algorithm using information extracted from EMR .…”

Maternal immune activation, central nervous system development and behavioral phenotypes

“…The trajectory taken by the developing CNS after exposure to prenatal MIA depends on other genetic and environmental factors that will ultimately determine the specific CNS disorder that emerges. In humans, the increased risk found from prenatal infectious exposers in families with a history of these disorders (Blomstrom et al, ; Clarke, Tanskanen, Huttunen, Whittaker, & Cannon, ), as well as in mothers with underlying autoimmune disorders, further support this hypothesis (Brown et al, ; Vinet et al, ; Wojcik et al, ; Xiang et al, ; Yengej et al, ).…”

“…Human data also comes in the form of a “pathogen‐free” model, that is, women with autoimmune disorders. Maternal Type 1 diabetes (Xiang et al, ), rheumatoid arthritis (Wojcik et al, ), systemic lupus (Vinet et al, ; Yengej, van Royen‐Kerkhof, Derksen, & Fritsch‐Stork, ), and thyroid disease (Brown et al, ) among others are independent risk factors for various disorders in offspring including ASD, SZ, attention deficit, and mood disorders. Finally, genome‐wide association studies and transcriptional profiles in patients with the underlying disorder have pointed to immune‐related pathways (Pouget et al, ; Schizophrenia Working Group of the Psychiatric Genomics, ; Sekar et al, ).…”