Vitamin D in Preterm and Full-Term Infants

Editor(s): Steven A. Abrams.

Focus
Vitamin D is a critical nutrient for bone health and needs to be provided to all infants whether via infant formula or as a supplement to breastfed infants or high-dose supplement to their mothers
Vitamin D in Preterm and Full-Term Infants
Key Insight
Vitamin D is essential for transcellular absorption of calcium and for skeletal health. Inadequate vitamin D in infants leads to poor bone mineralization and increased risk of rickets. Most guidelines recommend 400 IU daily of vitamin D to support bone health in preterm and full-term infants. Although cutaneous production of vitamin D occurs in infants, the use of sunblock and other factors limiting sun exposure make this an unreliable source. Therefore, recommendations for vitamin D intake are made assuming minimal or nonexistent cutaneous production of vitamin D. Not surprisingly, neonatal vitamin D status reflects maternal status. This knowledge has prompted current guidelines to recommend that vitamin D supplementation for infants is initiated as soon as possible.

Current knowledge
In the first weeks of life, calcium absorption occurs mainly via paracellular mechanisms that are not dependent on vitamin D. In preterm infants, absorption of vitamin D may be affected by various disease states, including malabsorptive disorders, such as cystic fibrosis. Cholestasis is another common problem in high-risk neonates and is associated with long-term use of parenteral nutrition. These highlight the importance of identifying the populations of mothers and infants who are at risk in order to ensure adequate vitamin D intake. Caution should be taken to ensure that the appropriate dose is given
and that accidental ingestion of high doses of vitamin D does not occur.


Practical implications
Currently, there is no clinical evidence to support the need for routine vitamin D supplementation for infants who are exclusively formula fed. In fully or partially breastfed infants, there are several methods for providing vitamin D. One is to administer the drops to the infant using a dropper. Vitamin D drops can also be placed directly on the breast or given as dissolvable film strips. Another approach is to have the lactating mother take a relatively high dose of vitamin D (6,400 IU daily) to ensure an adequate level of vitamin D in the breast milk.
However, adherence to guidelines varies widely between countries, highlighting the need for education for healthcare providers and families on the importance of providing sufficient vitamin D to infants.

Recommended reading
Roth DE, Abrams SA, Aloia J, Bergeron G, Bourassa MW, Brown KH, et al. Global prevalence and disease burden of vitamin D deficiency: A roadmap for action in low- and middleincome countries. Ann N Y Acad Sci. 2018 Oct;1430(1):44–79.

Key Messages

• Dietary vitamin D intake should be assured in all infants, preterm and full term, with     emphasis on adequate supplementation of infants who are receiving human milk.
• Usual total dietary intake level should be approximately 400 IU daily in healthy infants.
• There are multiple methods for providing vitamin D to infants these may be selected based on parental desires.

Keywords

Bone health · Calcium absorption · Vitamins

Abstract

Vitamin D is necessary for the active (transcellular) absorption of calcium and for skeletal health. Inadequate vitamin D in infants leads to increased risks of poor bone mineralization and ultimately rickets. Rickets is uncommon in full-term infants with a much higher risk in very premature infants. However, the primary cause of rickets in premature infants is a deficiency of calcium and phosphorus, not vitamin D. Available
research, as well as most guidelines, recommend an intake of 400 IU daily of vitamin D as adequate for bone health in preterm and full-term infants. Higher doses have not been consistently shown to have specific clinical benefits for healthy infants. There are no strong data to support either routine testing of serum 25-hydroxyvitamin D or targeting high serum 25-hydroxyvitamin D levels (e.g., 30 ng/mL) in healthy preterm or full-term infants. Vitamin D is commonly provided to infants via drops for breastfed babies or via infant formula, although alternative dosing approaches exist for breastfed infants, which some families may prefer. These include the use of drops placed on the mother’s breast, dissolvable doses, and high maternal doses (approximately 6,400 IU
daily). Infant formula contains vitamin D, and most infants will reach an intake from formula of about 400 IU daily within the first 2 months of life if they are consuming routine cow milkbased formula. Although vitamin D toxicity is very uncommon, caution should be used to avoid extremely concentrated high doses found in some commercially available drops. Infants with liver or kidney disease may need special attention to vitamin D intake and status. Further research is needed to define the role of vitamin D in non-bone health outcomes of infants and to identify methods to enhance compliance with
current recommendations for vitamin D intake in infants.

Vitamin D Physiology and Bone Health in Infants

Vitamin D is an essential nutrient for bone health in all individuals, including infants regardless of size or gestational maturity. Although other roles for vitamin D in health and disease exist, this discussion will focus on bone health, especially bone health in infants who do not have underlying endocrine disorders or severe nutritional diseases.
Vitamin D is critical for the transcellular absorption of calcium, via its active form, 1,25 dihydroxyvitamin D. Dietary vitamin D or vitamin D formed via solar exposure is converted in the liver to the circulating and primary storage, 25-hydroxyvitamin D (25[OH]D). The 25(OH)D is then transferred to the kidney where it is converted to 1,25 dihydroxyvitamin D. These physiological processes function normally in preterm and full-term infants who are otherwise healthy. A detailed review of vitamin D-related physiology can be found elsewhere [1].

Serum 25(OH)D in Infants

The role of serum 25(OH)D as a marker of vitamin D status has been extensively reviewed and discussed in a 2011 Institute of Medicine (IOM) report [2]. There are no recommendations either in that report or in any official American Academy of Pediatrics
(AAP) statement for routine screening of 25(OH)D level in healthy preterm or full-term infants [2–7]. It is critical to understand that 25(OH)D is not necessarily a marker of physiological vitamin D function as it is not the primary active form of vitamin D. Rather, its concentration in the serum is valuable as a means of assessing individual and population vitamin D status. Different values for serum 25(OH)D have been described
as “inadequate” or “deficient” in the literature. However, the adequate serum level indicated by the IOM and subsequently affirmed by the AAP of at least 20 ng/mL is the value that may be used for infants, both preterm and full term [2–6], pending further information clearly documenting nonbone health-related benefits to higher minimum levels. There are no data reliably establishing a value of 25(OH)D that is toxic, especially in infants. Values of > 100 ng/mL have been used to indicate toxicity without good clinical correlation of this or any specific toxic 25(OH)D level [7]. Nonetheless, uncommonly, vitamin D toxicity associated with hypercalcemia can exist in infants and may cause significant illness.
Values of serum 25(OH)D in the range often considered inadequate (12–20 ng/mL) are not generally associated with clinical evidence of vitamin D deficiency causing inadequate calcium absorption or rickets in infants. Vitamin D-deficient rickets is commonly seen with values of serum 25(OH)D below 12 ng/mL, although this is dependent on calcium intake as well as vitamin D status. In adults, data have suggested that values of 12–20 ng/mL are associated with normal efficiency of vitamin D-dependent calcium absorption, but data in infants are very limited as such studies are difficult to perform [2, 8]. In older children, values above about 12 ng/mL are associated with adequate calcium absorption, although there is a small, likely clinically insignificant, benefit to calcium absorption associated with increasing values [9].
In considering rickets, it is the relationship between vitamin D and calcium intake and status, as well as the status of other minerals, especially phosphorus and magnesium, which are crucial for the development of rickets. Because of this central role of mineral deficiency, rickets is not accurately described as being entirely a disease of vitamin D deficiency in any group of infants, especially preterm ones. Furthermore, some rare
disease states in which vitamin D function is not present are relatively effectively treated with high doses of oral calcium [10].

Vitamin D Intake and Function

The relationship between dietary intake of vitamin D and serum 25(OH)D levels has been evaluated both in preterm and full-term infants for many years. There are far fewer data relating 25(OH)D levels and bone mineral content or density in preterm infants or even fracture rates in these infants. Some data suggest a possible benefit for higher 25(OH)D levels on bone mineralization but need confirmation in larger trials and correlation with clinical events and outcomes [11–13] . There are no data indicating that doses of vitamin D of 400 IU daily, or serum 25(OH)D achieved with those doses, are associated with an increased risk of rickets or fractures in any population of preterm or full-term infants.



Most data in infants, both preterm and full term, do not specifically allow for an understanding of the relationship between body weight and dose-response of vitamin D intake. The IOM report considered these relationships related to age but not specifically for infants [2]. Although cutaneous production of vitamin D exists in infants, this too is generally minimally considered in most research as it is extremely hard to quantify, and the use of sunblock as well as other factors limiting sun exposure make this an unreliable source of vitamin D for infants. Recommendations for vitamin D intake, including those of the IOM [2], are generally done on the assumption that cutaneous conversion of pro-vitamin D to vitamin D in infants is minimal or nonexistent.
Calcium absorption in all populations is both by transcellular vitamin D-dependent and by paracellular vitamin D-independent mechanisms. There are very few data to indicate
the timing and relative role of these 2 mechanisms in newborns, whether preterm or full term. Numerous studies in preterm infants have shown a high level of calcium absorption, about 50% (compared to adults of 10–25% typically), in preterm infants. This includes infants fed human milk with or without fortification and those fed preterm formula across a broad range of calcium intakes [14, 15]. It has been suggested that these data indicate the likelihood that calcium absorption is primarily paracellular, not vitamin D dependent, in the first weeks of life in both preterm and possibly in full-term infants [16]. Transition to a greater proportion of calcium absorption by vitamin D-dependent active absorption may not occur for 1–2 months, but there are no data clearly defining this timing. Such research is nearly impossible to conduct, and we may never have a definitive answer to the timing and relative proportion of active versus passive calcium absorption in small infants and its relationship to dietary intake.

Preterm Infants

For preterm infants, it is generally found that a standard total intake of 400 IU daily will achieve a value of serum 25(OH)D above 20 ng/mL in most infants with averages well above 30ng/mL [12] ( Fig. 1 ). Some infants, especially those who have lower maternal vitamin D status at birth, may take longer to reach this value, but there are no suggestions of any clinical benefit to routinely giving higher doses [5]. A few infants receiving higher doses of vitamin D may have potentially toxic levels exceeding 100 ng/mL, but more information is needed



to evaluate this risk or any clinical correlates of relatively high vitamin D status in preterm infants [12].
However, in this regard, there are differences in recommendations between those commonly given in the USA and in Europe for vitamin D in preterm infants. European authorities and authors have generally recommended a dose of 800–1,000 IU vitamin D daily, whereas in the USA, 400 IU daily remains the standard recommendation [17]. This distinction is due to the perspective in European reviewers, based on limited-balance studies, that a lower calcium intake can be used with a higher vitamin D intake to increase total calcium absorption to needed levels to support preterm infant bone
mineralization. In the USA, it has been preferred to maintain a high calcium intake [4], and there are no current reasons to change recommendations or formulations of preterm infant products in the USA as there is no evidence of any harmful effects from calcium intake levels currently provided. Nonetheless, those who supplement preterm infants to a total intake of 800–1,000 IU daily may likely do so without serious concern for toxicity or need for close follow-up, given the long history of use of higher doses up to 1,000 IU daily in many countries in preterm infants.

Full-Term Infants

The requirements for vitamin D in full-term infants have been extensively investigated. Research has shown that the dose generally recommended for almost 100 years of 400 IU daily meets the needs of nearly all full-term infants, and it remains the recommendation for infants by the IOM and the AAP [2, 3] (Table 1). Even in populations in which values of 25(OH)D are low at birth, available data suggest that this dose will suffice for infants to adequately absorb calcium [18]. A recent study from Canada confirmed no effect on bone mineralization at 3 years of age of doses > 400 IU/day for breastfed infants, although higher 25(OH)D levels were achieved with higher doses [19]. Of greater concern was the unexpected finding that doses of vitamin D > 400 IU daily were associated with worse gross motor development at 6 months of age [20]. Caution
needs to be used in overinterpreting single or small studies such as this, but without evidence of benefit, use of high-dose vitamin D cannot be routinely recommended in full-term infants.
Although vitamin D is generally safe with negligible risk of acute toxicity with recommended dosing, there have been reports of toxicity, such as severe hypercalcemia associated with very high doses [21] . This may occur when caregivers mistakenly give highly concentrated vitamin D drops to infants. Although most vitamin D drops designed for infants provide 400 IU per dropper (generally about 0.5–1.0 mL liquid), products exist in the marketplace that provide 400 IU or more of vitamin D in each drop. If given a full 1 mL or more of products containing for example 400–1,000 IU per drop of supplement for a period of days, toxic doses could easily be given. As such, it is imperative to advise families about avoiding high doses or highly concentrated sources of vitamin D [22].

Dietary Sources of Vitamin D and Timing of Introduction

Because neonatal vitamin D status is reflective of maternal status, it has been suggested that it is best to start supplementation as early as is possible [2]. As such, whereas earlier recommendations in full-term infants suggested waiting until up to 6 weeks to allow lactation to become well-established, more recently, it is recommended that vitamin D be started within the first few weeks if not the first days of life.
One important reason for this is that it is easier and more reliably performed to teach families to properly give the drops to their breastfed infant while still in the hospital as it is less likely to be missed if begun in the hospital. In some hospitals,