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

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.