Abstract
BACKGROUND: Insulin resistance during pregnancy, while physiologically adaptive to enhance fetal nutrient supply, becomes pathological when excessive, contributing to low birth weight (LBW). The triglyceride-glucose (TyG) index, a biomarker of insulin resistance, predicts gestational complications, but its pathways to birth weight disparities remain unclear. This study investigates whether and to what extent first-trimester TyG index influences birth weight through preterm birth and gestational complications. METHODS: In this retrospective cohort study, 8,605 singleton pregnancies from a Chinese hospital (2015-2021) were analyzed. TyG index was calculated from first-trimester fasting glucose and triglycerides. Outcomes included gestational diabetes mellitus (GDM), hypertension, preeclampsia, preterm birth, LBW, macrosomia, and small/large-for-gestational-age (SGA/LGA). Logistic/multinomial regression assessed associations, followed by causal mediation analysis (R medflex package) to decompose direct/indirect effects. Models adjusted for maternal age, body mass index, education, parity, and diabetes family history. RESULTS: A 1-standard deviation TyG index increase was associated with elevated risks of gestational complications (i.e., GDM, gestational hypertension, and preeclampsia). Higher TyG index level also showed positive associations with adverse birth outcomes: preterm birth (OR = 1.20, 95% CI: 1.08-1.34), LBW (OR = 1.11, 95% CI: 1.00-1.24), and LGA (OR = 1.12, 95% CI: 1.05-1.21), but not with macrosomia or SGA. Mediation analysis revealed that individual gestational complications mediated 17.7% (GDM), 11.1% (gestational hypertension), and 18.9% (preeclampsia) of the TyG-LBW association, with a joint mediation effect of 37.5%. Preterm birth alone mediated 89.0% of the TyG index-LBW association. When considering all mediators together (preterm birth and gestational complications), the joint natural indirect effect was 1.12 (95% CI 1.05-1.18) with a null natural direct effect being 1.00 (95% CI 0.90-1.11), indicating full mediation. These mediation patterns were primarily evident among women with normal pre-pregnancy weight. Quartile-based comparisons (4th vs. 1st ) yielded similar results. CONCLUSION: Our findings highlight a significant association between the first-trimester TyG index and LBW with preterm birth emerging as the primary mediating pathway and gestational complications contributing partially to this relationship. Future research should explore whether interventions aimed at preventing preterm birth and gestational complications can mitigate the LBW risk.