Vitamin D in Newborn and Preterm Infants: Understanding The Roles, Forms, Metabolism, and Clinical Implications

Vitamin D in Newborn and Preterm Infants:
Understanding the Roles, Forms,

Metabolism, and Clinical Implications
Abstract
Vitamin D plays a pivotal role in the growth and development of newborns and preterm infants, with
significant implications for bone health, immune function, and overall metabolic stability. The various forms
of vitamin D, namely D2 (ergocalciferol) and D3 (cholecalciferol), differ in their origins and potency. The
active metabolites, particularly 25-hydroxyvitamin D (25-OH vitamin D), are crucial indicators of vitamin D
status in clinical practice. This review explores the history of vitamin D nomenclature, the metabolic
pathways involved in its hydroxylation, and the significance of its different forms in supplementation and
treatment. It also addresses the unique considerations for vitamin D management in newborns and preterm
infants, including the definitions of deficiency, insufficiency, and sufficiency. A comprehensive understanding
of these aspects is essential for optimizing clinical outcomes in this vulnerable population.
Introduction
Vitamin D is an essential nutrient that regulates calcium and phosphorus homeostasis, critical for bone
mineralization and overall health. Newborns and preterm infants are particularly vulnerable to vitamin D
deficiency due to various factors, including inadequate placental transfer, low dietary intake, and limited
sunlight exposure. This review provides an overview of the different forms of vitamin D, their metabolic
pathways, and the clinical considerations for managing vitamin D status in newborns and preterm infants.
History of Different Designations: D1, D2, and D3

Vitamin D was first identified in the early 20th century during research into the prevention of rickets, a
disease characterized by soft and weak bones. The different forms of vitamin D were discovered
sequentially, leading to their numerical designations:
Vitamin D1: This was the first form of vitamin D to be identified, though it is not a pure substance.
Vitamin D1 is a mixture of ergocalciferol (D2) and lumisterol. Due to its composite nature, it is no longer
used in modern clinical practice and has largely been forgotten in the context of vitamin D research.
Vitamin D2 (Ergocalciferol): Derived from plant sources and fungi, Vitamin D2 was the second form of
vitamin D to be discovered. It is produced by the irradiation of ergosterol and was used extensively in
early vitamin D supplementation efforts.
Vitamin D3 (Cholecalciferol): The third form identified, Vitamin D3 is synthesized in the skin of animals,
including humans, upon exposure to ultraviolet B (UVB) radiation from sunlight. It is the most potent
and widely used form of vitamin D in supplementation and treatment today.
Hydroxylation Metabolism
Vitamin D undergoes two main hydroxylation steps to become biologically active:
1. First Hydroxylation in the Liver: Vitamin D3 (cholecalciferol) is hydroxylated in the liver to form 25-
hydroxyvitamin D3 (25(OH)D3), also known as calcifediol. This metabolite is the main circulating form of
vitamin D and serves as the primary indicator of vitamin D status in the body.
2. Second Hydroxylation in the Kidneys: 25-hydroxyvitamin D3 is further hydroxylated in the kidneys to
produce 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), also known as calcitriol. Calcitriol is the biologically
active form of vitamin D that exerts its effects on calcium and phosphate metabolism, bone health, and
other physiological processes.
Vitamin D Metabolite Testing

In clinical practice, the most commonly tested metabolite is 25-hydroxyvitamin D (25(OH)D). This form is
preferred because it reflects total vitamin D from all sources (dietary, supplemental, and sunlight) and has a
relatively long half-life, making it a reliable indicator of vitamin D status.
Supplementation and Treatment

The form of vitamin D most commonly used for supplementation and treatment is Vitamin D3
(cholecalciferol) due to its superior potency and efficacy in raising and maintaining serum 25-
hydroxyvitamin D levels compared to Vitamin D2. In cases of deficiency or insufficiency, Vitamin D3 is the
preferred form, administered either orally or intramuscularly, depending on the clinical scenario.
Considerations for Newborns and Preterm Infants

Newborns
Newborns, particularly those who are exclusively breastfed, are at a heightened risk of vitamin D deficiency
due to the low vitamin D content in human milk (~25 IU/L). Although newborns receive some vitamin D
through placental transfer during pregnancy, the levels are often insufficient, especially if the mother is
deficient. For this reason, the American Academy of Pediatrics (AAP) recommends that all breastfed infants
receive 400 IU of vitamin D3 daily, starting within the first few days of life.
Newborns who are formula-fed typically receive adequate vitamin D through fortified formulas, which
contain about 400 IU of vitamin D per liter. However, mixed-fed infants may still require supplementation to
ensure they meet the recommended daily intake.
Preterm Infants
Preterm infants, defined as those born before 37 weeks of gestation, have even greater challenges with
vitamin D status. They miss a significant portion of placental vitamin D transfer, which primarily occurs in the
third trimester. As a result, preterm infants are born with lower stores of vitamin D, and their immature
organs further complicate the metabolism and utilization of this crucial nutrient.
Preterm infants are at a high risk for developing conditions such as osteopenia of prematurity (OOP), a form
of metabolic bone disease characterized by decreased bone mineral content. To prevent these
complications, higher doses of vitamin D supplementation are often necessary. Guidelines suggest that
preterm infants receive between 400-800 IU of vitamin D3 daily, depending on their gestational age, weight,
and specific clinical needs【44†source】【45†source】.
In cases of severe deficiency (vitamin D levels below 20 ng/mL), higher doses, such as 1,000-2,000 IU daily,
may be recommended for a period of 4-8 weeks to rapidly increase serum vitamin D levels【43†source】
【44†source】. Once adequate levels are achieved (above 30 ng/mL), a maintenance dose of 400-800 IU
daily can be resumed【45†source】.
Moreover, preterm infants may require regular monitoring of their serum 25-hydroxyvitamin D levels to
ensure adequacy and to adjust supplementation as they grow and develop. These infants are often cared for
in neonatal intensive care units (NICUs), where their nutritional status, including vitamin D levels, can be
closely monitored and managed.
Definitions of Deficiency, Insufficiency, and Sufficiency

The status of vitamin D is typically categorized based on serum 25-hydroxyvitamin D levels. These categories
are important for guiding clinical decisions regarding supplementation and treatment. Below is a table
summarizing the definitions:
Serum 25- Serum 25-

Vitamin D Hydroxyvitamin D Level Hydroxyvitamin D Level
Status (ng/mL) (nmol/L) Clinical Implications
Deficiency < 20 ng/mL < 50 nmol/L Increased risk of rickets,

osteomalacia, poor bone
health
Insufficiency 20-29 ng/mL 50-75 nmol/L Suboptimal bone health,

potential risk of bone disorders
Sufficiency ≥ 30 ng/mL ≥ 75 nmol/L Adequate for maintaining bone

health and metabolic function
Understanding these thresholds is crucial for managing vitamin D status in newborns and preterm infants,
ensuring they receive the appropriate level of supplementation to support optimal growth and
development.
Summary
Vitamin D is critical for the health and development of newborns and preterm infants, with important roles
in bone mineralization, immune function, and overall growth. The different forms of vitamin D, particularly
D2 and D3, have distinct properties and clinical applications. The metabolism of vitamin D involves crucial
hydroxylation steps in the liver and kidneys, with 25-hydroxyvitamin D serving as the primary indicator of
vitamin D status. Supplementation with Vitamin D3 is the most effective strategy for preventing and treating
deficiency, particularly in at-risk populations such as preterm infants. Understanding the nuances of vitamin
D metabolism and status assessment is essential for optimizing clinical outcomes in newborns and preterm
infants.
References
1. Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3), 266-281.
2. Wagner, C. L., & Greer, F. R. (2008). Prevention of rickets and vitamin D deficiency in infants, children,
and adolescents. Pediatrics, 122(5), 1142-1152.
3. Misra, M., Pacaud, D., Petryk, A., Collett-Solberg, P. F., & Kappy, M. (2008). Vitamin D deficiency in
children and its management: review of current knowledge and recommendations. Pediatrics, 122(2),
398-417.
4. Basatemur, E., & Sutcliffe, A. (2015). Vitamin D deficiency in the newborn. Archives of Disease in
Childhood - Fetal and Neonatal Edition, 100(1), F70-F73.
5. Munns, C. F., Shaw, N., Kiely, M., Specker, B. L., Thacher, T. D., Ozono, K., ... & Bishop, N. J. (2016). Global
consensus recommendations on the prevention and management of nutritional rickets. Journal of
Clinical Endocrinology & Metabolism, 101(2), 394-415.

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Vitamin D in Newborn and Preterm Infants:

Understanding the Roles, Forms,

History of Different Designations: D1, D2, and D3

Vitamin D Metabolite Testing

Supplementation and Treatment

Considerations for Newborns and Preterm Infants

Definitions of Deficiency, Insufficiency, and Sufficiency

Serum 25- Serum 25-

Deficiency < 20 ng/mL < 50 nmol/L Increased risk of rickets,

Insufficiency 20-29 ng/mL 50-75 nmol/L Suboptimal bone health,

Sufficiency ≥ 30 ng/mL ≥ 75 nmol/L Adequate for maintaining bone

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