Chronic inflammatory states, steroid hormone exposure, and stress can affect iron-related biology, an essential micronutrient needed for infant growth and normal brain development. This project will investigate the novel hypothesis that some of the disabling effects of a stressful prenatal environment are mediated by undermining the placental transfer of maternal iron, which results in the subsequent depletion of iron stores in the growing infant. A nonhuman primate model will be used to determine how gestational stress impairs the placental transfer, sequestering, and use of iron by the young infant.
One aim focuses on the timing of the gestational disturbance, comparing the effects of maternal stress during early, mid, or late pregnancy. To quantify placental transfer and bioavailability of iron in the neonate, an innovative approach with stable iron isotopes will be employed, contrasting absorption and transfer of 57Fe provided orally to 58Fe infused intravenously into the pregnant female. Iron-sensitive hematological measures will then be monitored in the developing infants from the stressed and undisturbed control pregnancies to prove that the postnatal iron deficiency is temporally associated with the occurrence of abnormal brain and renal functions. Based on previous findings in anemic monkeys, neural dysfunction will be indexed by the protein and metabolite profile of cerebrospinal fluid using Western blot and nuclear Magnetic Resonance Spectroscopy techniques. To further demonstrate the clinical significance of these deficits, the effects of prenatal stress and anemia on renal functioning observed in other species will be verified. When infants are 8 months of age, measures of glomerular filtration rate and renal sympathetic input will be obtained. A second study will support the veracity of iron mediation hypothesis by showing that oral iron supplementation during pregnancy can lessen the effects of prenatal stress on the developing infants. The two studies are comprised of 126 mother-infant pairs of rhesus monkeys, with the behavior and physiology of each infant evaluated prospectively from birth across the first year of life. This research will contribute to the growing awareness about the formative role of the fetal period in laying the foundation for postnatal health. Demonstrating that gestational stress affects iron homeostasis would reveal a deficit amenable to treatment. Iron deficiency has a broad public health significance because it is the most prevalent single nutrient deficiency worldwide.

Public Health Relevance

Maternal stress, illness, and inflammatory processes during pregnancy can impair fetal growth, affect the likelihood of premature birth and obstetrical complications, and increase the risk for a number of postnatal behavioral and health problems in children. This project will investigate how gestational stress interferes with the placental transfer and utilization of maternal iron by the young baby, an important micronutrient needed for growth and normal brain development. Studies on iron deficiency are of particular relevance to the higher risk infants of low SES, anemic and stressed mothers, as well as of significance for babies from pregnancies complicated by diabetes and hypertension. The findings may reveal deficits that are amenable to prevention and treatment.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Raju, Tonse N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Arts and Sciences
United States
Zip Code
Rao, Raghavendra; Ennis, Kathleen; Lubach, Gabriele R et al. (2018) Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey. Nutr Neurosci 21:40-48
Dosch, Natalie C; Guslits, Elyssa F; Weber, Morgan B et al. (2016) Maternal Obesity Affects Inflammatory and Iron Indices in Umbilical Cord Blood. J Pediatr 172:20-8
Rendina, Danielle N; Lubach, Gabriele R; Coe, Christopher L (2016) Gestational Timing of Prenatal Disturbance and Fetal Sex Determine the Developmental Outcomes. Neonatology 109:314-20
Kapoor, Amita; Lubach, Gabriele R; Ziegler, Toni E et al. (2016) Hormone levels in neonatal hair reflect prior maternal stress exposure during pregnancy. Psychoneuroendocrinology 66:111-7
Coe, Christopher L; Lubach, Gabriele R (2014) Vital and vulnerable functions of the primate placenta critical for infant health and brain development. Front Neuroendocrinol 35:439-46
Short, Sarah J; Lubach, Gabriele R; Shirtcliff, Elizabeth A et al. (2014) Population variation in neuroendocrine activity is associated with behavioral inhibition and hemispheric brain structure in young rhesus monkeys. Psychoneuroendocrinology 47:56-67
Kapoor, Amita; Lubach, Gabriele; Hedman, Curtis et al. (2014) Hormones in infant rhesus monkeys' (Macaca mulatta) hair at birth provide a window into the fetal environment. Pediatr Res 75:476-81
Coe, Christopher L; Lubach, Gabriele R; Busbridge, Mark et al. (2013) Optimal iron fortification of maternal diet during pregnancy and nursing for investigating and preventing iron deficiency in young rhesus monkeys. Res Vet Sci 94:549-54
Rao, Raghavendra; Ennis, Kathleen; Oz, Gulin et al. (2013) Metabolomic analysis of cerebrospinal fluid indicates iron deficiency compromises cerebral energy metabolism in the infant monkey. Neurochem Res 38:573-80
McLimore, Heather M; Phillips, Alyssa K; Blohowiak, Sharon E et al. (2013) Impact of multiple prenatal risk factors on newborn iron status at delivery. J Pediatr Hematol Oncol 35:473-7

Showing the most recent 10 out of 16 publications