Prenatal alcohol-related alterations in maternal, placental, neonatal, and infant iron homeostasis

Abstract

Background: Prenatal alcohol exposure (PAE) is associated with postnatal iron deficiency (ID), which has been shown to exacerbate deficits in growth, cognition, and behavior seen in fetal alcohol spectrum disorders. However, the mechanisms underlying PAE-related ID remain unknown.

Objectives: We aimed to examine biochemical measures of iron homeostasis in the mother, placenta, neonate, and 6.5-month-old infant.

Methods: In a prenatally recruited, prospective longitudinal birth cohort in South Africa, 206 gravidas (126 heavy drinkers and 80 controls) were interviewed regarding alcohol, cigarette, and drug use and diet at 3 prenatal visits. Hemoglobin, ferritin, and soluble transferrin receptor (sTfR) were assayed twice during pregnancy and urinary hepcidin:creatinine was assayed once. Infant ferritin and hemoglobin were measured at 2 weeks and 6.5 months and sTfR was measured at 6.5 months. Histopathological examinations were conducted on 125 placentas and iron transport assays (iron regulatory protein-2, transferrin receptor-1, divalent metal transporter-1, ferroportin-1, and iron concentrations) were conducted on 63.

Results: In multivariable regression models, prenatal drinking frequency (days/week) was related to higher maternal hepcidin and to sequestration of iron into storage at the expense of erythropoiesis in mothers and neonates, as evidenced by a lower hemoglobin (g/dL)-to-log(ferritin) (ug/L) ratio [mothers: raw regression coefficient (β) = -0.21 (95% CI: -0.35 to -0.07); neonates: β = -0.15 (95% CI: -0.24 to -0.06)]. Drinking frequency was also related to decreased placental ferroportin-1:transferrin receptor-1 (β = -0.57 for logged values; 95% CI: -1.03 to -0.10), indicating iron-restricted placental iron transport. At 6.5 months, drinking frequency was associated with lower hemoglobin (β = -0.18; 95% CI: -0.33 to -0.02), and increased prevalences of ID (β = 0.09; 95% CI: 0.02-0.17) and ID anemia (IDA) (β = 0.13; 95% CI: 0.04-0.23). In causal inference analyses, the PAE-related increase in IDA was partially mediated by decreased neonatal hemoglobin:log(ferritin), and the decrease in neonatal hemoglobin:log(ferritin) was partially mediated by decreased maternal hemoglobin:log(ferritin).

Conclusions: In this study, greater PAE was associated with an unfavorable profile of maternal-fetal iron homeostasis, which may play mechanistic roles in PAE-related ID later in infancy.

Keywords: FAS; FASD; ID; IDA; fetal alcohol spectrum disorders; fetal alcohol syndrome; iron deficiency; iron deficiency anemia; placenta; prenatal alcohol exposure.

FIGURE 1

Causal mediation analyses. Directed acyclic graphs demonstrating: (A) maternal hemoglobin-to-log(ferritin) ratio as a mediator of the relation between heavy alcohol exposure and neonatal hemoglobin-to-log(ferritin) ratio. (B) Maternal hepcidin as a mediator of the relation between drinking frequency and 6.5-month infant hemoglobin. (C) Neonatal hemoglobin-to-log(ferritin) ratio as a mediator of the relation between drinking frequency and infant iron deficiency anemia at 6.5 months. Values are β (95% CI) from marginal structural models adjusting for covariates chosen from exposure-mediator and exposure-outcome regression models using 10% change-in-estimate criteria as described in the Methods section. [(A) maternal age, food insecurity (53), prenatal methamphetamine use, and infant age; (B) weeks gestation at time of hepcidin measurement, prenatal iron supplementation, prenatal methamphetamine use, food insecurity, and 6.5-month serum B12; and (C) gravidity, prenatal cigarette smoking, prenatal methamphetamine use, prenatal iron supplementation, food insecurity, infant age, and weeks formula given]. Interaction effects for drinking days/week were modeled as drinking frequency increasing from 0 to 3 days/week. †P ≤ 0.10; *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.