Abstract
BackgroundThymic size in early infancy predicts subsequent survival in low-income settings. The human thymus develops from early gestation, is most active in early life and is highly sensitive to malnutrition. Our objective was to test whether thymic size in infancy could be increased by maternal and/or infant nutritional supplementation.MethodsThe Early Nutrition and Immune Development (ENID) Trial was a randomized 2 × 2 × 2 factorial, partially blinded trial of nutritional supplementation conducted in rural Gambia, West Africa. Pregnant women (N = 875) were randomized to four intervention groups (iron-folate (standard care), multiple micronutrients, protein energy or protein energy + multiple micronutrients at ‘booking’ (mean gestational age at enrolment = 13.6 weeks, range 8–20 weeks) until delivery. The iron-folate and multiple micronutrient arms were administered in tablet form and the protein energy arms as a lipid-based nutritional supplement. All intervention arms contained 60 mg iron and 400 μg folic acid per daily dose. From 24 to 52 weeks of age, infants from all groups were randomized to receive a daily lipid-based nutritional supplement, with or without additional micronutrients. Thymic size was assessed by ultrasonography at 1, 8, 24 and 52 weeks of infant age, and a volume-related thymic index calculated. Detailed data on infant growth, feeding status and morbidity were collected.ResultsA total of 724 (82.7%) mother-infant pairs completed the trial to infant age 52 weeks. Thymic size in infancy was not significantly associated with maternal supplement group at any post-natal time point. Infants who received the daily LNS with additional micronutrients had a significantly larger thymic index at 52 weeks of age (equivalent to an 8.0% increase in thymic index [95% CI 2.89, 13.4], P = 0.002). No interaction was observed between maternal and infant supplement groups.ConclusionsA micronutrient-fortified lipid-based supplement given in the latter half of infancy increased thymic size, a key mediator of immune function. Improving the micronutrient status of infants from populations with marginal micronutrient status may improve immune development and survival.Trial registrationISRCTN registry (controlled-trials.com) Identifier: ISRCTN49285450
Highlights
Thymic size in early infancy predicts subsequent survival in low-income settings
Despite recent progress, infant and child mortality remains at unacceptably high levels in low- and middle-income countries (LMICs)
Most deaths are caused by infections and it has been estimated that malnutrition contributes to 45% of all these deaths by limiting immune competence [1]
Summary
Thymic size in early infancy predicts subsequent survival in low-income settings. Our objective was to test whether thymic size in infancy could be increased by maternal and/or infant nutritional supplementation. Interventions to improve nutritional status during pregnancy have been associated with better birth outcomes, including neonatal survival [2, 3] possibly through nutritionally mediated influences on infant immune development. The thymus starts to develop very early in gestation with fetal T cells detectable as early as 8 weeks. It reaches its peak size in proportion to total body weight very soon after birth and declines thereafter. Thymic size assessed in early infancy has been shown to predict subsequent survival in low-income settings [5,6,7]
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