Prenatal stress perturbs fetal iron homeostasis in a sex specific manner

Abstract

The adverse effects of maternal prenatal stress (PS) on child's neurodevelopment warrant the establishment of biomarkers that enable early interventional therapeutic strategies. We performed a prospective matched double cohort study screening 2000 pregnant women in third trimester with Cohen Perceived Stress Scale-10 (PSS-10) questionnaire; 164 participants were recruited and classified as stressed and control group (SG, CG). Fetal cord blood iron parameters of 107 patients were measured at birth. Transabdominal electrocardiograms-based Fetal Stress Index (FSI) was derived. We investigated sex contribution to group differences and conducted causal inference analyses to assess the total effect of PS exposure on iron homeostasis using a directed acyclic graph (DAG) approach. Differences are reported for p < 0.05 unless noted otherwise. Transferrin saturation was lower in male stressed neonates. The minimum adjustment set of the DAG to estimate the total effect of PS exposure on fetal ferritin iron biomarkers consisted of maternal age and socioeconomic status: SG revealed a 15% decrease in fetal ferritin compared with CG. Mean FSI was higher among SG than among CG. FSI-based timely detection of fetuses affected by PS can support early individualized iron supplementation and neurodevelopmental follow-up to prevent long-term sequelae due to PS-exacerbated impairment of the iron homeostasis.

Figure 1

Putative link of PS with iron homeostasis and maternal–fetal heart rate coupling. A proposed simplified model of the hepcidin–placental–ferroportin axis based on the articles of Cortes et al. and Lobmaier et al.: Hepcidin is the key regulator within this system. By binding to ferroportin, it prevents the release of iron into the bloodstream and therefore the synthesis of the transport protein transferrin and the storage protein ferritin. Hepcidin levels are influenced strongly by inflammatory processes, especially the cytokine IL-6. Another possible pathway influencing the child's stress phenotype is assumed to be realized by interference in the coupling between maternal and fetal heart rate (mHR, fHR) as seen during maternal expiration. PSS perceived stress scale, FSI fetal stress index.

Figure 2

Sex-dependent group difference in cord blood serum ferritin levels. GEE model the main effects of sex and study group and their interaction (sex*group) on ferritin. GEE ferritin: group*sex p = 0.038. GEE generalized estimating equations, SG stressed group, CG control group.

Figure 3

Maternal age, socioeconomic status, and education as confounding factors within the prenatal stress trajectory. Directed acyclic graph analysis of the relationships between maternal and fetal antenatal, perinatal, and postnatal exposures, covariates, and outcomes. PSS perceived stress scale, FSI fetal stress index, HR heart rate, BMI body-mass index, IVF in-vitro-fertilization.

Figure 4

Recruitment flow chart. SG stressed group, CG control group, PSS perceived stress scale, SGA small for gestational age, IUGR intrauterine growth restriction.