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800 IU versus 400 IU per day of vitamin D3 in term breastfed infants: a randomized controlled trial from an LMIC

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Abstract

This open-label, block-randomized controlled trial compared the effect of 800 IU/day and 400 IU/day of oral vitamin D3 supplementation in reducing vitamin D insufficiency (VDI) among healthy-term breastfed infants at 14 weeks of postnatal age. All eligible infants were randomized to receive either 800 or 400 IU/day of oral vitamin D3 (starting within the first week until 14 weeks). The primary outcome was the proportion of infants with VDI (25-OH-D < 20 ng/ml) at 14 weeks. Secondary outcomes were vitamin D deficiency (VDD, < 12 ng/ml), severe VDD (< 5 ng/ml), anthropometry, biochemical or clinical rickets, and any adverse events related to vitamin D toxicity (VDT). Among 102 enrolled infants, the distribution of baseline variables (including cord 25-OH-D levels; 13.0 versus 14.2 ng/ml) was similar in both groups. On intention-to-treat analysis, the proportions of infants with VDI at 14 weeks were significantly lower in the 800 IU group compared to those in the 400 IU group [24% versus 55%; RR 0.44; 95% CI: 0.25–0.76]. The proportions of infants with elevated parathormone (6% versus 26.5%; p = 0.012) and severe VDD (0% versus 12.2%; p = 0.033) were significantly lower in the 800 IU group. Clinical rickets developed in three (6.2%) infants in the 400 IU group. No infant developed VDT.

     Conclusions: Daily oral supplementation with 800 IU of vitamin D3 resulted in an almost 50% reduction in the proportion of infants with VDI and prevented the occurrence of severe VDD at 14 weeks of age compared to 400 IU with no evidence of vitamin D toxicity.

     Trial Registration: Clinical Trial Registry of India (CTRI/2019/02/017374).

What is Known:

• Breastfeeding is the ideal source of nutrition for healthy-term breastfed infants; however, vitamin D content of breastmilk is suboptimal.

• AAP recommends daily oral supplementation of 400 IU of vitamin D to all healthy-term breastfed infants; however, trials from high-income countries support insufficiency of this dose in maintaining serum 25-OH-D levels >20 ng/ml with no such information from low-middle-income countries.

What is New:

• 800 IU/day of oral vitamin D3 supplementation among term breastfed infants significantly reduces vitamin D insufficiency at 14 weeks’ age as compared to the recommended dose of 400 IU/day.

• This higher supplemental dose is safe with no evidence of vitamin D toxicity.

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Abbreviations

ALP:

Alkaline phosphatase

CLIA:

Chemiluminescence immuno-assay

CI:

Confidence interval

DEXA:

Dual energy X-ray absorptiometry

GH:

Gestational hypertension

GDM:

Gestational diabetes mellitus

HICs:

High-income countries

IU:

International unit

LMIC:

Low-middle-income countries

Ng/ml:

Nanogram per milliliter

PTH:

Serum parathormone

RR:

Relative risk

25-OH-D:

Serum 25-hydroxyvitamin D

VDD:

Vitamin D deficiency

VDI:

Vitamin D insufficiency

VDT:

Vitamin D toxicity

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Funding

No external funding was available; however, the cost of the investigations was bore by the institute and the drug was supplied in-kind contribution by Cipla, India.

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Author notes

  1. Bharti Yadav and Neeraj Gupta contributed equally.

Authors and Affiliations

  1. Department of Neonatology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India

    Bharti Yadav, Neeraj Gupta, Rohit Sasidharan, Sivam Thanigainathan & Arun Singh

  2. Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

    Purvi Purohit & Praveen Sharma

  3. Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

    Kuldeep Singh

Authors
  1. Bharti Yadav
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  2. Neeraj Gupta
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Contributions

Bharti Yadav: conceptualized and designed the study (with NG), recruited patients, compiled the data, drafted the initial manuscript, and reviewed and revised the manuscript. Neeraj Gupta: planned the study, supervised the collection, analyzed and interpreted the data, did critical revision and finalization of the manuscript. Rohit Sasidharan: conceptualized and designed the study, coordinated the sample collection, followed up these patients, and critically reviewed the manuscript for important intellectual content. Sivam Thanigainathan: participated in data analysis and critically reviewed the manuscript for important intellectual content. Purvi Purohit: participated in study design, processed the biochemical samples of bone mineral panel, vitamin D, and serum PTH. Kuldeep Singh: supervised the design of study, generated the randomization sequence, and critically revised the manuscript. Praveen Sharma: supervised the processing of biochemical samples, analyzed the results, and did critical revision of the manuscript. Arun Singh: participated in data analysis and critically reviewed the manuscript for important intellectual content. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. NG is the guarantor of the paper.

Corresponding author

Correspondence to Neeraj Gupta.

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Conflict of interest

The authors declare no competing interests.

Disclaimer

The supplier of the drug or its representative has no role in the study design, conduct, analysis, and manuscript preparation.

Clinical trial registry name and number

The study was registered with Clinical Trial Registry of India CTRI/2019/02/017374.

Ethical clearance

The Ethics Committee of All India Institute of Medical Sciences (AIIMS), Jodhpur, approved the study protocol.

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Communicated by Daniele De Luca

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Yadav, B., Gupta, N., Sasidharan, R. et al. 800 IU versus 400 IU per day of vitamin D3 in term breastfed infants: a randomized controlled trial from an LMIC. Eur J Pediatr 181, 3473–3482 (2022). https://doi.org/10.1007/s00431-022-04533-5

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