Trimethylamine N-Oxide Metabolites in Early Pregnancy and Risk of Gestational Diabetes: A Nested Case-Control Study

Objectives: This study aimed to investigate the associations between trimethylamine N-oxide (TMAO) and related metabolites in early pregnancy and the risk of gestational diabetes mellitus (GDM). Design: A prospective cohort of 22,302 pregnant women from 2010 to 2012 in Tianjin, China, was used to perform a nested case-control study. A total of 243 women with GDM and 243 women without GDM matched by maternal age (+/- 1 year) were used as cases and controls, respectively. Conditional logistic regression and restricted cubic spline were used to examine the full-range risk associations between individual TMAOs metabolites at the first antenatal care visit with GDM. Trimethylamine conversion ratio (TMA(R)) was defined as trimethylamine (TMA)/its precursors, and trimethylamine N-oxide conversion ratio (TMAO(R)) was defined as TMAO/TMA. An additive interaction between high TMA(R) and low TMAO(R) indicates a state of TMA accumulation, and a mathematical interaction between high TMA(R) and high TMAO R indicates accumulation of TMAO. Results: TMA was linearly associated with GDM, whereas TMA precursors and TMAO were inversely associated with GDM with clear threshold effects, i.e., 16 nmol/mL for TMAO, 200 nmol/mL for betaine, 112 nmol/mL for L-carnitine, and 110 and 270 nmol/mL for cholinechloride (a U-shaped relationship). Copresence of TMA(R) >0.35 and TMAO(R) <0.15 was associated with a markedly higher OR (11.16; 95% CI, 5.45 to 22.8), compared with TMA(R) >0.35 only (OR = 1.71; 95% CI, 0.42 to 6.95) or TMAO(R) <= 0.15 only (OR = 2.06; 95% CI, 1.09 to 3.90), with a significant additive interaction. However, the mathematical interaction was nonsignificant. Conclusions: TMAO metabolites in the early pregnancy were associated with the risk of GDM, whereas TMA was more likely to play a causal role in GDM.