First‐Trimester Maternal Gut Microbiome and Small Vulnerable Newborns: A Prospective Cohort Study

ABSTRACT Objectives To investigate the relationship between the first trimester gut microbiome and small vulnerable newborns (SVN). Setting Rural low‐ and middle‐income country: Bangladesh. Population 213 women were enrolled during the first trimester of pregnancy as part of the NICHD Global Network for Women's and Children's Health registry, Bangladesh. Methods Observational study of the maternal gut microbiome and birth outcomes. Blood and stool samples were collected at enrollment. Birth outcomes were recorded within 72 h of delivery. Random forest machine learning models trained on microbiome data were used to predict SVN or first‐trimester maternal features of interest. Hold out sets were used to test model accuracy. Main Outcome Measures SVN (born preterm, low birth weight, or small for gestational age). Results The birth outcome SVN ( n = 106) was discriminated from non‐SVN ( n = 107) using a microbiome‐trained random forest model (AUC = 0.653, 95% CI 0.518–0.789). The microbiome also predicted the inflammatory markers plasma alpha‐1‐acid glycoprotein and faecal calprotectin (AUC = 0.742, 95% CI: 0.616–0.868 and AUC = 0.793, 95% CI: 0.680–0.905, respectively), while micronutrient concentrations, anaemia, C‐reactive protein and the presence of atypical Enteropathogenic E. coli were not reliably predicted. Higher alpha‐1‐acid glycoprotein was significantly associated with SVN (aOR = 1.98; 95% CI: 1.04–3.85) whereas calprotectin was not. Conclusions In this prospective cohort, first‐trimester maternal gut microbiome composition showed modest discrimination for SVN and a marker of systemic inflammation. These findings support further investigation of early pregnancy microbiome–inflammation pathways in fetal growth restriction and preterm birth.