Scairati, Roberta (2025) A late-gestation three-cluster phenotype analysis in gestational diabetes: insights from the emerge randomized, placebo-controlled trial of metformin. [Tesi di dottorato]

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Abstract

Aim: Gestational diabetes mellitus (GDM) is characterized by profound alterations in glucose and lipid metabolism, yet the impact of combined maternal lipid profiles on fetal growth and treatment response remains unclear. This study aimed to identify late-pregnancy lipid phenotypes in women with GDM and to examine their associations with neonatal anthropometry and perinatal outcomes, and whether the effects of metformin differ by lipid phenotype. Methods: A secondary analysis of the EMERGE phase 3 randomized, double-blind, placebo-controlled trial was conducted, including 399 GDM pregnancies with complete 38-week lipid data. Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were standardized to z-scores and clustered using unsupervised k-means to derive maternal lipid phenotypes. Neonatal outcomes included detailed anthropometry, small- and large-for-gestational-age (SGA, LGA), macrosomia and neonatal hypoglycaemia. Maternal outcomes included hypertensive disorders and postpartum glycaemic status. Associations between lipid clusters, treatment allocation (metformin vs placebo) and outcomes were assessed using linear and logistic regression, adjusted for maternal BMI and HbA1c, with treatment-by-cluster interaction terms. Results: Three distinct lipid phenotypes were identified: hypolipidaemic (n = 203, 50.9%), proatherogenic (n = 87, 21.8%), and favourable (n = 109, 27.3%), with significantly different lipid z-scores across clusters (p < 0.001). Infants of mothers in the proatherogenic cluster had the highest birthweight (p = 0.004) and arm circumference (p = 0.018), and higher rates of LGA (p = 0.046) and macrosomia (p = 0.019). Conversely, the favourable cluster showed lower birthweight and arm circumference and more SGA infants (p = 0.027). At 38 weeks, triglycerides were higher in women randomized to metformin than placebo (p = 0.004). Within the hypolipidaemic cluster, metformin was associated with shorter crown–heel length (p = 0.013) and higher odds of appropriate-for-gestational-age birth (p = 0.040). In the favourable cluster, metformin was associated with smaller arm circumference (p = 0.006), while in the proatherogenic cluster metformin exposure was associated with higher neonatal hypoglycaemia (17% vs 2.5%, p = 0.035). No consistent differences were observed in maternal postpartum glycaemic outcomes across clusters. Conclusions: Late-pregnancy lipid phenotypes in GDM delineate metabolically distinct subgroups of fetal growth, ranging from SGA-prone to overgrowth-prone profiles. Metformin shows modest but phenotype-specific effects on neonatal size, tending to promote appropriate-for-gestational-age birth in low-lipid profiles and to attenuate overgrowth in more lipid-replete phenotypes. Maternal lipid profiling may complement glycaemic markers to support more individualized, biology-informed treatment strategies in GDM.

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