Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study

Abstract

Objective: This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D).

Research design and methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7-10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children's individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D.

Results: A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only.

Conclusions: Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.

Figure 1

Growth in early life. A: Trajectories of body size measurements of 50 randomly selected TEDDY subjects and the mean (loess) curves for weight and height. B: Description of the two-phase piecewise linear modeling of growth in early life. C: Fitted growth curves of weight and height from the Bayesian two-phase piecewise linear modeling for four randomly selected subjects.

Figure 2

Study cohort. A: Flow chart of the TEDDY cohort and the study cohort. B: Survival curve of the development of IA. C: Survival curve of progression to T1D from initial seroconversion.

Figure 3

Forest plots of HR and 95% CI from multiple Cox PH regression analyses of effect of weight (A) and height (B) growth parameters, including gestational age–adjusted birth measurement, on the risk of IA, IAA-first IA, and GADA-first IA. Duration of exclusive breastfeeding, HLA-DR-DQ genotype, family history of T1D, sex, and country of residence were included in the Cox models. mo, months.

Figure 4

Forest plots of HR and 95% CI from multiple Cox PH regression analyses of effect of weight (A) and height (B) growth parameters, including gestational age–adjusted birth measurement, on the risk of progression to T1D from IA and from subgroup analysis stratified by the type of first-appearing autoantibody (IAA only, GADA only, or multiple autoantibodies). Duration of exclusive breastfeeding, age at the development of IA, type of first-appearing autoantibody (if applicable), HLA-DR-DQ genotype, family history of T1D, sex, and country of residence were included in the Cox models. mo, months.