Behavioral consequences at 5 y of neonatal iron deficiency in a low-risk maternal-infant cohort

Abstract

Background: Iron is critical to the developing brain, but fetal iron accretion is compromised by several maternal and pregnancy-related factors. Little consideration has been given to the long-term neurologic consequences of neonatal iron deficiency, especially in generally healthy, low-risk populations.

Objective: We aimed to investigate the association between neonatal iron deficiency and neurologic development at 2 and 5 y of age.

Design: We measured umbilical cord serum ferritin concentrations in the prospective maternal-infant Cork BASELINE (Babies after SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints) Birth Cohort. Lifestyle and clinical data were collected from 15 weeks of gestation to 5 y of age. Standardized neurologic assessments were performed at 2 y [Bayley Scales of Infant Development/Child Behavior Checklist (CBCL)] and 5 y (Kaufman Brief Intelligence Test/CBCL).

Results: Among 697 maternal-infant pairs, median (IQR) cord ferritin concentrations were 200.9 (139.0, 265.8) µg/L; 8% had neonatal iron deficiency (ferritin <76 µg/L). Using fully adjusted models, there was no association between neonatal iron deficiency and cognitive or behavioral outcomes at 2 or 5 y. We conducted an a priori sensitivity analysis in 306 high-risk children, selected using known risk factors for neonatal iron deficiency (smoking/obesity/cesarean section delivery/small-for-gestational age birth). In this high-risk subgroup, children with iron deficiency at birth (12%) had similar cognitive outcomes, but the behavioral assessments showed higher internalizing [9.0 (5.3, 12.0) compared with 5.0 (3.0, 10.0), P = 0.006; adjusted estimate (95% CI): 2.8 (0.5, 5.1), P = 0.015] and total [24.5 (15.3, 40.8) compared with 16.0 (10.0, 30.0), P = 0.009; adjusted estimate (95% CI): 6.6 (0.1, 13.1), P = 0.047] problem behavior scores at 5 y compared with those born iron sufficient.

Conclusions: We have demonstrated lasting behavioral consequences of neonatal iron deficiency in high-risk children from our generally healthy, low-risk maternal-infant cohort. Although larger investigations are warranted, this study provides strong association data to suggest that interventions and strategies targeting the fetal and neonatal period should be prioritized for the prevention of iron deficiency and associated neurologic consequences.

Keywords: behavior; birth cohort; cesarean section; externalizing problems; internalizing problems; iron deficiency; maternal health; maternal obesity; neonatal; newborn infants.