Adequacy of Maternal Iron Status Protects against Behavioral, Neuroanatomical, and Growth Deficits in Fetal Alcohol Spectrum Disorders

Abstract

Fetal alcohol spectrum disorders (FASD) are the leading non-genetic cause of neurodevelopmental disability in children. Although alcohol is clearly teratogenic, environmental factors such as gravidity and socioeconomic status significantly modify individual FASD risk despite equivalent alcohol intake. An explanation for this variability could inform FASD prevention. Here we show that the most common nutritional deficiency of pregnancy, iron deficiency without anemia (ID), is a potent and synergistic modifier of FASD risk. Using an established rat model of third trimester-equivalent binge drinking, we show that ID significantly interacts with alcohol to impair postnatal somatic growth, associative learning, and white matter formation, as compared with either insult separately. For the associative learning and myelination deficits, the ID-alcohol interaction was synergistic and the deficits persisted even after the offsprings’ iron status had normalized. Importantly, the observed deficits in the ID-alcohol animals comprise key diagnostic criteria of FASD. Other neurobehaviors were normal, showing the ID-alcohol interaction was selective and did not reflect a generalized malnutrition. Importantly ID worsened FASD outcome even though the mothers lacked overt anemia; thus diagnostics that emphasize hematological markers will not identify pregnancies at-risk. This is the first direct demonstration that, as suggested by clinical studies, maternal iron status has a unique influence upon FASD outcome. While alcohol is unquestionably teratogenic, this ID-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is more common in alcohol-abusing pregnancies than generally appreciated. Iron status may also underlie the associations between FASD and parity or socioeconomic status. We propose that increased attention to normalizing maternal iron status will substantially improve FASD outcome, even if maternal alcohol abuse continues. These findings offer novel insights into how alcohol damages the developing brain.

Maternal micronutrient consumption periconceptionally and during pregnancy: a prospective cohort study

“…This relationship is consistent with a belief held by some women that low-level consumption of alcohol is associated with low risk, particularly in the context of an otherwise healthy lifestyle (30) . While there is some research evidence to support the idea that good maternal nutrition can ameliorate some of the effects of fetal exposure to alcohol (31)(32)(33) , current medical advice recommends abstinence during pregnancy as the safest policy.…”

Health Care for Youth Involved with the Correctional System

“…45 Some evidence suggests that nutritional deficiencies during pregnancy magnify the deleterious effects of alcohol on the brain. 46,47 These children have substantial problems with memory and a poor understanding of the consequences of behavior, and they tend to be easily influenced by peers and make poor decisions in life. 48,49 For these reasons, youth with fetal alcohol spectrum disorders (FASDs) may be more likely to commit offenses and be detained.…”

Maternal iron nutriture as a critical modulator of fetal alcohol spectrum disorder risk in alcohol-exposed pregnancies

“…Rufer et al (2012) created a rat model wherein mothers received an iron sufficient (IS) (100 ppm) or iron deficient (ID) (20 ppm) diet; the ID mothers exhibited low liver iron stores but were not anemic, modeling the common condition in pregnancy. Alcohol exposure (0, 3.5, 5 g/kg) temporally targeted the fetal brain growth spurt, which is especially vulnerable to alcohol during the human third trimester and in rat postnatal days 4 through 9 (West and Goodlett 1990).…”

“…In PAE offspring, maternal ID reduced postnatal growth and, in males, interacted with ID to further impede growth, consistent with the clinical findings of Carter et al (2007, 2012) and suggesting a role for iron status in PAE’s growth inhibition. Maternal ID and PAE synergized to impair associative learning in the offspring, not only in a simple cerebellum-dependent task (delay eyeblink conditioning), but also in associative tasks involving other brain regions including contextual fear conditioning (amygdala and hippocampus), auditory-cued conditioning (amygdala), and trace eyeblink conditioning (cerebellum and hippocampus) (Huebner et al 2015; Rufer et al 2012). The iron-alcohol interaction was selective, as other behaviors including open field behavior, gait, balance, and muscle strength were unaffected by the ID-alcohol interaction (Rufer et al 2012).…”

“…The ID-alcohol combination also increased neuronal apoptosis, and ID-alcohol interacted to significantly reduce cerebellar myelin content (Rufer et al 2012) to levels beyond the impact of ID or alcohol alone (Georgieff 2011; Wilhelm and Guizzetti 2016). Because the learning and cellular deficiencies in PAE rats are lessened in the IS offspring compared to ID offspring, this work suggests that maternal iron adequacy can partially ameliorate alcohol’s neurodevelopmental damage (Huebner et al 2015).…”