Vitamin D prophylaxis in infancy

We looked at existing recommendations and supporting evidence on the effectiveness of vitamin D supplementation in infancy for reducing vitamin D deficiency and for preventing rickets and infections. We also looked at optimal dose of vitamin D and the age until which vitamin D supplementation is beneficial. We conducted a literature search up to the 17th of July 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported. A daily dose of 400 international units of vitamin D in infants has shown to be effective for improving bone health and preventing rickets. Evidence is more robust in groups of infants and children at risk. Vitamin D supplementation is well tolerated, and not associated with toxicity. Higher doses have not shown to add benefit while it could potentially cause toxic blood levels and hypercalcemia. Adequate levels of vitamin D might not be achieved with lower daily doses. Universal vitamin D supplementation starting shortly after birth, regardless of the mode of feeding and until 12 months of age, is strongly recommended. Beyond 12 months of age vitamin D supplementation is recommended only in groups of children at risk.


Introduction
The World Health Organization (WHO) European Region is developing a new pocket book for primary health care for children and adolescents in Europe. This article is part of a series of reviews, which aim to summarize the existing recommendations and the most recent evidence on preventive interventions applied to children under 5 years of age to inform the WHO editorial group to make recommendations for health promotion in primary health care. In this article, we looked at existing recommendations and supporting evidence on the effectiveness of vitamin D supplementation in reducing vitamin D deficiency and in preventing rickets and infections.

Why is vitamin D important?
Vitamin D is essential in the metabolism of calcium and phosphate, skeletal growth and bone health, but is also involved in other functions such as the modulation of the function of activated B and T lymphocytes, insulin production, the secretion of thyroid stimulating hormone and myocardial contractility [1].

Context
Vitamin D from the diet is limited, the main natural source of vitamin D being from the action of the sunlight on the skin. However, several factors such as cultural practices and sun protection for prevention of cancer has conditioned vitamin D deficiency and rickets to reappear as a global health problem. Low concentration of vitamin D in breast milk, and the recommendation of keeping newborns and infants out of direct sun exposure are all factors that contribute to the risk of vitamin D deficiency in infants [2]. Vitamin D deficiency is usually defined as serum levels of 25-hydroxyvitamin D lower than 50 nmol/l (equivalent to 20 ng/ml), while serum levels superior to 75 nmol/l (equivalent to 30 ng/ml) ensure adequate metabolic demands and health [3].

Key questions
1. Is vitamin D supplementation in infancy effective in reducing vitamin D deficiency and in preventing rickets and infections? (Table 1) 2. Which dose of vitamin D is more effective and safer in preventing rickets in infancy? 3. Until which age is prophylactic vitamin D beneficial to infants?

Search methods and selected manuscripts
We described the search methods, data collection and data synthesis in the second paper of this supplement [4].
The search was conducted on the 17th of July 2019, using the search term "vitamin D". Vitamin D supplementation in infants is addressed by WHO and provided by the e-Library of Evidence for Nutrition Actions (eLENA). The search on the US Preventive Services Task Force (USPSTF) returned five entries, but none of them included the paediatric population, and vitamin D in children was not identified as a recommendation in progress. From the PrevInfad workgroup (Spanish Association of Primary Care Pediatrics), recommendations were found for Vitamin D prophylaxis during infancy and early childhood, although dated from August 2009. Two guidelines were identified from the National Institute for Health and Care Excellence (NICE).
The search in the Cochrane library using the date of publication from 2010 as filter yielded 63 reviews and 12 protocols. By screening the titles and abstracts, we included two systematic reviews. Twelve additional reviews were published before 2010 and we identified one relevant systematic review from 2007. We identified three protocols from which the findings of the corresponding systematics reviews would be relevant for this article. We contacted the authors of three protocols; all of them replied that their systematic review was expected to be published in the coming months. We updated the search on the 10th of October 2019, none of them were published in the Cochrane library, but we had access to the unpublished findings of the review by Huey et al.
We identified two additional studies by hand search of the references of included papers. One paper on global consensus recommendations on prevention and management of nutritional rickets, and one systematic review gathering the evidence on vitamin D requirements in infancy from trials published between 2009 and 2016.
All the included manuscripts for revision in this article are displayed in Table 2.

Existing recommendations
We summarized the existing recommendations and the strength of recommendations as per their authors in Table 3.
The Global consensus recommendations were established by the initiation of the European Society for Pediatric Endocrinology, based on evidence up to 2014 [17]. The expert panel included members from the Pediatric Endocrine Society, the Asia Pacific Pediatric Endocrine Society, the Japanese Society for Pediatric Endocrinology, the Sociedad Latino-Americana de Endocrinología Pediátrica, the Australasian Pediatric Endocrine Group, the Indian Society for Pediatric and Adolescent Endocrinology, the African Society for Pediatric and Adolescent Endocrinology, the Chinese Society of Pediatric Endocrinology and Metabolism, the British Nutrition Society, and the European Society for Pediatric Gastroenterology Hepatology and Nutrition.

Risk factors for vitamin D deficiency
Most recommendations refer to groups of infants and children at high risk for vitamin D deficiency. Identified risk factors for vitamin D deficiency are [6,17,19]: In newborns and small infants: o Maternal vitamin D deficiency: mothers with restricted sun exposure, with dark skin colour, who wear veil, multiparous, with low vitamin D intake

Existing evidence
Three Cochrane reviews assessed the effectiveness of vitamin D supplements for improving bone health [11], on linear growth and non-communicable diseases [14], and for preventing infections [10] in children. An older Cochrane review looked at the effectiveness of vitamin D supplements for preventing rickets [12]. Although published in 2007, we included this older review in this summary as it constitutes part of the supporting evidence for current recommendations [5,6]. Five studies were identified by the global consensus panel and served as reference for developing their recommendations on vitamin D supplementation for the prevention of rickets and osteomalacia [17]. Among them, one study (Beser 1994) was included in the Lerch 2007 Cochrane review, two studies [20,21] were not included but published prior to the publication of the identified Cochrane systematic reviews for this summary, and two studies were published afterwards [22,23]. The aim of the Mimouni 2017 systematic review was to review more recent publications (between 2009 and 2016) for new evidence related to vitamin D dosages in healthy infants [18].

Vitamin D supplementation for preventing rickets and improving bone health
The Lerch 2007 Cochrane review looked at the effects of several interventions (vitamin D supplementation, vitamin D and calcium supplementation, or increased sun exposure) for preventing nutritional rickets in term born children [12]. Four trials were identified and included children aged between 9 months and 2 years from China, France and Turkey. In the trial conducted in Turkey, none of the 300 children who received 400 international units (IU) per day of vitamin D developed rickets versus 14 children out of 372 from the control group (relative risk [RR] 0.04; 95% confidence interval [CI] 0 to 0.71; one trial). In one trial conducted in China, authors compared a combined intervention of vitamin D  • Lerch 2007 -Interventions for the prevention of nutritional rickets in term born children [12] • Yu 2017 -The effects of oral vitamin D supplementation on linear growth and non-communicable diseases among infants and children younger than five years of age (Protocol) [13]. Access to the unpublished stage of the systematic review: Huey 2019 [14] • Tan 2018 -Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health (Protocol) [15] • Pharande 2015 -Vitamin D supplementation for prevention of vitamin D deficiency in preterm and low birth weight infants (Protocol) [16] Others In addition to the Turkish study already included in Lerch 2007, two studies were identified by the general consensus panel that looked at the effect of vitamin D supplementation for preventing rickets [17]. A randomized controlled trial (RCT) conducted in Chinese children showed that vitamin D supplementation of 100, 200 or 400 IU per day prevented radiographic signs of rickets at 6 months of age [21]. Similarly, two-year surveillance data from Canada showed that there was no case of radiographically confirmed rickets among infants receiving regular vitamin D supplementation of 400 IU per day from birth [22].  [5] 2019 "Current evidence suggests that vitamin D supplements may be effective in preventing rickets, particularly for infants and children who may be at higher risk due to limited sun exposure or those with darker skin pigmentation, however further research is needed before specific recommendations can be made." (Category 2 intervention) a Recommendations were graded as 1 for strong recommendation or 2 for weak recommendation; and quality of evidence was assessed as ⊕ ⊕ ⊕ high quality (prospective cohort studies or randomized controlled trials at low risk of bias), ⊕ ⊕ ○ for moderate quality (observational studies or trials with methodological flaws, inconsistent or indirect evidence), and ⊕○○ for low quality (case series or non-systematic clinical observations) [17] As there is limited evidence from studies looking at radiological or clinical signs of rickets as outcome, we included studies that looked at other related outcomes such as levels of 25OHD and bone mineral density. The Winzenberg 2010 Cochrane review looked at the effectiveness of vitamin D supplementation for at least 3 months versus placebo in healthy children aged from 1 month to < 20 years for improving bone mineral density [11]. Six RCTs (541 children receiving vitamin D and 343 children receiving placebo) were included for meta-analysis. These studies included children aged between eight and 17 years from Hong Kong, Finland, Pakistan and Lebanon. With a followup of one to 2 years, vitamin D had no effect on total body bone mineral density (

Vitamin D supplementation and linear growth
The Huey 2019 Cochrane review (yet unpublished) evaluated the effects of vitamin D supplementation on linear growth [14]. For all the outcomes addressed by this review, 60 RCTs or quasi-RCTs were included. Most of them were conducted in the US, India, Finland, Canada, and Iran. The duration of follow-up for the different interventions ranged from a few days to 24 months. The main findings were as follows.
Vitamin D supplementation in children was not associated with any significant differences in linear growth (mean length/height, in cm) at the end of the supplementation period or at longterm follow-up: vitamin D versus placebo (three RCTs, 120 participants; low certainty evidence), higher-dose versus lower-dose vitamin D (eight RCTs, 240 participants; very low certainty evidence), or vitamin D with micronutrients versus micronutrients alone (one RCT, 25 participants; moderate certainty evidence). Vitamin D supplementation in children was not associated with any significant difference in height-for-age Z scores (mean HAZ scores) when compared to placebo (one RCT, 1258 participants; high certainty evidence) or to lower-dose vitamin D (two RCTs, 24 participants; very low certainty evidence).
Vitamin D supplementation in children compared to placebo was not associated with any significant difference in the prevalence of stunting (one RCT, 1282 participants; high certainty evidence).

Vitamin D supplementation and other non-communicable diseases outcomes
The yet unpublished Cochrane review aimed to evaluate the effect of vitamin D supplementation in children on atopic diseases (this is asthma, recurring wheeze, dermatitis, and/or rhinitis) and other noncommunicable diseases (any type of cancer, type 1 and type 2 diabetes mellitus, insulin resistance, and other autoimmune disorders) as secondary outcomes [14]. They found no significant differences on atopic diseases, and they found no studies assessing other non-communicable diseases.

Vitamin D supplementation for preventing infections
The Yakoob 2016 Cochrane review looked at the effectiveness of vitamin D supplementation versus placebo or no intervention in children under 5 years of age for preventing infections from RCTs [10]. There was probably no benefit of vitamin D supplementation on the incidence of radiologically confirmed pneumonia (RR 1.06 [95%CI 0.89 to 1.26]; two trials, 3134 participants; moderate certainty evidence) or diarrhoea (no effect, however meta-analysis was not possible for this outcome; two trials, 3134 participants). From one trial (3046 participants), vitamin D supplementation may not have effect on all-cause mortality (RR 1.43 (95%CI 0.54 to 3.74); low certainty evidence) or on cause-specific mortality (RR 1.50 [95%CI 0.42 to 5.30]; low certainty evidence).

Different dosages of vitamin D supplementation for preventing rickets
Three studies identified by Munns et al. [17] compared the effect of different dosages of vitamin D supplementation [20,21,23]. In their consensus statement, the expert panel added that "Among infants and toddlers with 25OHD levels < 50 nmol/L for whom daily vitamin D supplementation may not be ideal, intermittent bolus doses of 50 to 100 000 IU every 3 months hold promise, although a comprehensive understanding of the safety and efficacy of this approach remains to be studied" [17]. The Mimouni 2017 review [18] identified 11 manuscripts from nine RCTs looking at the effect of different doses of vitamin D supplementation in healthy infants [23][24][25][26][27][28][29][30][31][32][33], including one of the three studies identified by Munns et al. [23]. Authors concluded that "there is no additional evidence that larger, more generous amounts of daily vitamin D beyond the recommended 400 IU daily dose, affects any long-term significant outcome. It even appears that larger amount may lead to serum 25(OH) D concentrations that have been reported to be potentially associated with adverse effects." The basic characteristics and main findings of the 13 studies identified by these two reviews are summarized in Table 4.

Duration of administration of vitamin D supplementation
While most of the sources recommend vitamin D supplementation in all infants for the first 12 months of age, there is a lack of strong evidence supporting this duration of administration of 12 months. Assessment of risk factors including the overall vitamin D intake through milk and foods containing vitamin D and sun exposure seem key factors leading to the established recommendations.

Adverse effects
Vitamin D supplementation was well tolerated according to the trials included in Winzenberg 2010 [11]. None of the included trials in Yakoob 2016 reported any adverse effect of vitamin D supplementation, although one infant was found to have high concentration of vitamin D in one trial with no clinical repercussion, and two children had toxic concentrations of vitamin D in another included trial [10]. The recent, yet unpublished Cochrane review evaluated adverse events of oral vitamin D and found that there were no significant differences in the risk of hypercalciuria, hypercalcemia, nor hyperphosphatemia between oral vitamin D and either placebo, lower doses of vitamin D or micronutrients [14].

Summary of findings
All infants should receive vitamin D for improving bone health and preventing rickets, starting shortly after birth, regardless of the mode of feeding. Evidence is more robust to support this recommendation in groups of infants and children at risk.
There is probably no benefit of universal vitamin D supplementation in infants on the incidence of radiologically confirmed pneumonia or diarrhoea. A daily dose of 400 international units of vitamin D in infants has shown to be effective for preventing rickets. It is well tolerated, and not associated with toxicity. Higher doses have not shown to add benefit while it could potentially cause toxic blood levels and hypercalcemia. Adequate levels of vitamin D might not be achieved with lower daily doses. Universal vitamin D supplementation until 12 months of age is strongly recommended. Beyond 12 months of age vitamin D supplementation is recommended only in groups of children at risk. There is however a lack of evidence supporting this cut off of 12 months, so this age cut off seems arbitrary.
Acknowledgments I am very grateful to María Jesús Esparza, Laura Reali, and Gottfried Huss for carefully reviewing and providing valuable feedback for each article. I am also grateful to Ralf Weigel and Gottfried Huss for proofreading the final version of this document.

About this supplement
This article has been published as part of BMC Pediatrics Volume 21, Supplement 1 2021: Defined preventive interventions for children under five years of age: evidence summaries for primary health care in the WHO European region. The full contents of the supplement are available at https://bmcpediatrics.biomedcentral.com/articles/supplements/volume-21supplement-1.
Author's contributions SJ was identified as the researcher in the development of the synthesis of evidence and writing the report. For each selected topic on preventive interventions, SJ defined the key questions, established and run the literature search, screened the returned manuscripts for eligibility, extracted data and summarized the existing recommendations and supporting evidence. The principal advisors of this project were Dr. Gottfried Huss, MPH General Secretary of ECPCP, Project-Coordinator and Prof. Ralf Weigel, Friede Springer endowed professorship of Global Child Health, Witten/Herdecke University (scientific advice). The author(s) read and approved the final manuscript. Same as above Body composition (by anthropometric measurements and from the dualenergy X-ray absorptiometry measurements): no differences between the 3 groups.
"However when all infants were combined, there was a weak correlation between 25OHD measurements and lean body mass, although this correlation may have only reflected subtle differences in outdoors physical activity rather than differences because of treatment group allocation."