Risk factors for iron deficiency in neonates

Introduction

Iron, although critically necessary, is both a good and a bad actor because excess unbound iron may be toxic. The physiologic window between the extremes of iron deficiency (ID) and excess is narrow. Official guidelines for identifying and managing iron status in ill neonates are based on limited research data and thus are nonspecific and incomplete, especially with parenteral iron administration.

Eighty percent of placental-fetal iron transfer occurs during the last trimester. Preterm newborns without benefit of the third trimester are at great risk for ID, having accrued limited iron endowment to sustain the greater iron needs for rapid postnatal growth rates and critical neurodevelopment. In addition to prematurity, fetal conditions impacting iron status include multiple gestation and large or small for gestational age (LGA or SGA). Advances in clinical neonatal intensive care unit (NICU) practice patterns impact iron status in ill newborns. Even at term, maternal ID, alcohol intake, diabetes, obesity, hypertension, and/or placental dysfunction can substantially impair fetal iron endowment. Medically underserved populations are at risk for infantile ID and impaired fetal iron endowment. Although not currently a recognized diagnosis, perhaps neonatologists should recognize neonates with low fetal iron endowment (i.e., diagnose congenital ID).

Defining the controversies

Iron is critically necessary for sustaining most body processes and in neonates to sustain both growth and neurodevelopment. Developing ID in early life can impair neurodevelopment, cognition, and behavior. Although critically necessary, iron is both a good and a bad actor because excess unbound iron is toxic. In ill neonates, free unbound iron is particularly problematic and may raise risk for infection and generate excessive oxidant stress that may worsen lung disease.

Recent advances in contemporary NICU practice may either negatively or positively impact iron status in ill newborns. Both delayed umbilical cord clamping (DCC) and red blood cell (RBC) transfusions increase total body iron. Conversely, iron demands are increased by greater postnatal phlebotomy losses relative to body weight, especially with extremely low gestation preterm neonates. Iron demands also rise with transfusion preventative strategies by erythropoietic stimulating agents (ESAs) and with recent nutritional strategies to improve postnatal growth rates.

Maternal diagnoses that impair fetal iron endowment are increasingly common contributors to preterm birth and/or ill NICU neonates. Even in apparently well-appearing term neonates, maternal or placental conditions such as severe maternal ID, alcohol intake, diabetes, obesity, hypertension, and/or placental dysfunction can substantially impair fetal iron endowment, promoting congenital ID. Fetal conditions place NICU neonates at risk for congenital ID, prematurity, multifetal gestation, LGA, or SGA. Medically underserved populations at risk for infantile ID anemia, such as low socioeconomic status (SES), maternal psychosocial stress, and/or ethnic minority status, are also at risk for congenital ID ( Fig. 7.1 ). Multiple risk factors may be summative in term neonates. Although not current practice, it is important for clinicians to recognize and diagnose congenital ID.

Traditional tests of iron status in neonates may be challenging for clinicians to interpret because normal and threshold levels differ from those in older individuals. However, thresholds are known. In part due to limited data, official guideline recommendations for iron management in at-risk neonates are incomplete. Recommendations lack both clarity and specificity for managing early ID in at-risk neonates. Recommendations may be out of date based on contemporary NICU practice. Thus NICU and outpatient pediatric providers are left to approach iron status in at-risk infants without evidenced-based guidelines.

Perinatal iron physiology

If maternal iron status is normal and the placenta functional, fetal iron endowment rises in proportion to gestational age and birth weight, with 80% of iron endowed in the last trimester. At birth, healthy term newborns have accrued 75 mg of iron per kg of body weight. Normally, fetal iron is endowed at 1.6 to 2.0 mg/kg daily. Because 80% of fetal body iron resides within hemoglobin (Hb), iron is prioritized for erythropoiesis above other tissue needs. Most term neonates born after uncomplicated pregnancies have sufficient iron stores to support erythropoiesis and growth for only 4 to 6 months. ^,

Iron status is sensed in the liver by the master iron regulator, hepcidin, and controlled through cell-surface intestinal iron transporters making intestinal iron absorption efficient in infancy. When circulating hepcidin levels fall, iron enters the circulation, coming from both intestinal iron absorption and liver stores. Maternal hepcidin levels normally fall to meet the sixfold higher pregnancy needs for iron absorption facilitating placental iron transfer. Higher maternal liver hepcidin (1) inhibits her iron absorption, (2) blocks iron trafficking from her reticular-endothelial system, and (3) blocks placental-fetal transfer. Obesity or rapid weight gain in pregnancy may cause sufficient inflammation to raise maternal hepcidin and limit enteral absorption, placental transfer, and fetal iron delivery. Diabetes is a novel example in that the apical placenta transferrin receptor may be glycosylated in its active site, specifically inhibiting placental iron transfer. Even with normal maternal iron, placental dysfunction, especially with hypertension sufficiently severe for fetal growth restriction, may also limit placental iron transfer. Other inflammatory maternal, placental, and/or fetal mechanisms may force the iron balance into congenital ID that is unable to offset interventions that promote iron sufficiency (see Fig. 7.1 ).

Risk factors for congenital, neonatal, and infantile ID

Because congenital ID may lead to infantile ID, risks are similar and can be demarcated relating to (1) maternal supply, (2) dysfunctional placental logistics, and/or (3) fetal factors representing demands (see Fig. 7.1 ).