Maternal stress and fetoplacental cortisol regulation in small-for-gestational-age newborns.

Objective: Previous research has identified an association between maternal stress, fetal growth and the expression of glucocorticoid-related genes in the placenta, particularly 11-beta hydroxysteroid dehydrogenase-2 (HSD11β2). However, to date, no studies have simultaneously explored the relationships between maternal stress, placental expression and methylation of HSD11β2, and fetal cortisol metabolites according to fetal growth. The aim of the present study was to evaluate the association between perceived antenatal maternal stress, the expression and methylation of the placental HSD11β2 gene, fetal cortisol metabolites in amniotic fluid and birth weight.

Methods: This nested case-control study, which was part of a large prospective cohort study, was conducted at two maternofetal medicine units in Barcelona, Spain (BCNatal: Hospitals Clinic and Sant Joan de Déu). We enrolled singleton pregnancies and classified neonates as small-for-gestational-age (SGA) if their birth weight was below the 10^th percentile (n = 343) or as appropriate-for-gestational-age (AGA) controls (n = 399). The Perceived Stress Scale (PSS) and the State-Trait Anxiety Inventory (STAI) scores were obtained to assess maternal stress and anxiety levels. We analyzed placental HSD11β2 RNA expression (n = 44 SGA and 28 AGA) and DNA methylation levels (n = 89 SGA and 34 AGA), and fetal cortisol metabolites and the activity of metabolizing enzymes in amniotic fluid (n = 135 SGA and 78 AGA) using liquid chromatography-tandem mass spectrometry.

Results: Median maternal perceived stress (PSS, 23 (interquartile range (IQR), 17-28) vs 20 (IQR, 15-26); P < 0.001) and median anxiety state (STAI-state, 19.0 (IQR, 14.0-29.0) vs 16.0 (IQR, 11.0-24.0); P < 0.001) scores were significantly higher in the SGA group compared with the control group. SGA cases showed lower median placental HSD11β2 RNA expression (Δ Ct, 50.5 (IQR, 21.6-106.0) vs 92.7 (IQR, 62.3-118.0); P = 0.013) with similar DNA methylation levels (mean ± SD, 10.7 ± 3.0% vs 11.0 ± 2.8%; P = 0.648) compared with AGA controls. Analysis of amniotic fluid revealed altered cortisol metabolism in SGA fetuses, with increased median 5α-tetrahydrocortisol concentration (SGA, 0.09% (IQR, 0.06-0.15%) vs controls, 0.07% (IQR, 0.05-0.11%); P = 0.020) and activity of its related enzyme (5α-reductase activity in SGA, 0.19% (IQR, 0.14-0.31%) vs controls, 0.17% (IQR, 0.12-0.22%); P = 0.007), together with a decrease in median 6-hydroxycortisol concentration (SGA, 0.09% (IQR, 0.06-0.11%) vs controls, 0.11% (IQR, 0.08-0.12%); P < 0.001) and activity of its related enzyme (CYP3A7 activity in SGA, 0.19% (IQR, 0.11-0.25%) vs controls, 0.24% (IQR, 0.17-0.33%); P < 0.001).

Conclusions: SGA pregnancy is associated with high perceived maternal stress and dysregulated fetoplacental cortisol metabolism. These results deepen our understanding of the pathophysiology of SGA and highlight the potential benefit of intervention to mitigate maternal stress. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.