Placental DNA methylation dysregulation underlies fetal growth restriction associated with maternal pre-pregnancy underweight

While maternal obesity is a well-established risk factor for adverse fetal outcomes, the impact of pre-pregnancy underweight remains incompletely characterized. This study aimed to investigate the association between maternal pre-pregnancy underweight and fetal growth restriction (FGR) and, more critically, to elucidate the underlying mechanisms. We conducted a retrospective cohort study of 7,504 singleton deliveries at a tertiary obstetric and gynecology hospital in Shanghai. Genome-wide DNA methylation profiling (using GM-seq, a bisulfite-free genomic methylation sequencing approach) and transcriptomic analysis (via RNA-seq) were conducted on placental samples obtained from FGR cases (n = 5) and healthy controls (n = 4). A significant dose-dependent association was observed between maternal pre-conception underweight (BMI (body mass index) < 18.5 kg/m2) and FGR, with an aOR (adjusted odds ratio) of 1.57 (95% confidence interval (CI): 1.31–1.88; p value < 0.001). We identified 128 DMRs (differentially methylated regions) specifically associated with FGR in the context of maternal pre-pregnancy underweight. Notably, expression levels of two DMR-associated genes TSTD1 and KCNG2, which are implicated in placental energy metabolism, were significantly dysregulated in FGR placentas from underweight mothers. These results demonstrated that DNA methylation and transcriptional alterations of genes involved in placental energy metabolism may link maternal pre-pregnancy underweight to FGR. Thus, our findings highlighted the importance of pre-conception nutritional interventions to optimize fetal development.