Perinatal iron deficiency as an early risk factor for schizophrenia

ABSTRACT

Growing evidence indicates that a suboptimal intrauterine environment confers risk for schizophrenia. The developmental model of schizophrenia posits that aberrant brain growth during early brain development and adolescence may interact to contribute to this psychiatric disease in adulthood. Although a variety of factors may perturb the environment of the developing fetus and predispose for schizophrenia later, a common mechanism has yet to be elucidated. Micronutrient deficiencies during the perinatal period are known to induce potent effects on brain development by altering neurodevelopmental processes. Iron is an important candidate nutrient to consider because of its role in energy metabolism, monoamine synthesis, synaptogenesis, myelination, and the high prevalence of iron deficiency (ID) in the mother-infant dyad. Understanding the current state of science regarding perinatal ID as an early risk factor for schizophrenia is imperative to inform empirical work investigating the etiology of schizophrenia and develop prevention and intervention programs. In this narrative review, we focus on perinatal ID as a common mechanism underlying the fetal programming of schizophrenia. First, we review the neural aberrations associated with perinatal ID that indicate risk for schizophrenia in adulthood, including disruptions in dopaminergic neurotransmission, hippocampal-dependent learning and memory, and sensorimotor gating. Second, we review the pathophysiology of perinatal ID as a function of maternal ID during pregnancy and use epidemiological and cohort studies to link perinatal ID with risk of schizophrenia. Finally, we review potential confounding phenotypes, including nonanemic causes of perinatal brain ID and future risk of schizophrenia.

KEYWORDS:

• Brain
• brain development
• iron
• iron deficiency
• perinatal iron deficiency
• psychiatric disease
• schizophrenia
• two-hit hypothesis

Acknowledgments

The authors acknowledge the editorial assistance of Ms. Alexandra Prince.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Cited studies from Dr. Rao’s lab are supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [grant number R01HD89989]. AMM is supported by the University of Minnesota Medical Scientist Training Program [grant number T32GM008244] (PI: Shimizu).

Notes on contributors

Andrea M. Maxwell

Andrea M. Maxwell is a trainee in the University of Minnesota Medical Scientist Training Program.

Raghavendra B. Rao

Raghavendra B. Rao is a Professor in the Department of Pediatrics and Director of the Division of Neonatology at University of Minnesota Medical School. He is a Core Faculty and Chair of the Scientific Advisory Committee of the Center for Neurobehavioral Development and a Senior Advising Faculty in the Graduate Program in Neuroscience, both at University of Minnesota, Twin Cities Campus.