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Natural Medicine Journal

July 6, 2023

Does High-Dose Vitamin D Supplementation Early in Life Decrease the Risk of Psychiatric Symptoms Later in Childhood?

Results from a randomized, controlled trial

Michelle Loy

MD, FAAP
Yes
Findings regarding high-dose vitamin D supplementation remain conflicting but reveal a potential role in mental health.

Reference

Sandboge S, Räikkönen K, Lahti-Pulkkinen M, et al. Effect of vitamin D3 supplementation in the first 2 years of life on psychiatric symptoms at ages 6 to 8 years: a randomized clinical trial. JAMA Netw Open. 2023;6(5):e2314319.

Study Objective

  1. To determine the impact of high-dose vs standard-dose vitamin D3 supplementation during the first 2 years of life on psychiatric symptoms at ages 6 to 8 years
  2. To determine whether the impact of high- vs standard-dose supplementation is different in children with lower vs higher maternal vitamin D3 levels

Key Takeaway

In this randomized, controlled trial (RCT) of 346 children, those randomized to receive higher-dose vitamin D3 supplementation (1,200 IU/day) in the first 2 years after birth showed decreased risk for clinically significant internalizing problems later in childhood compared to those randomized to receive the standard dose (400 IU/day).

Design

Randomized, double-blind clinical trial

Participants

The study was a long-term follow-up of the double-blind RCT Vitamin D Intervention in Infants (VIDI) conducted at a single center in Helsinki, Finland. VIDI originally included 987 term-born infants (2013–2014); 546 of these individuals participated in the follow-up at ages 6 to 8 years (2020–2021), among whom 346 individuals had data on parent-reported psychiatric symptoms. Researchers analyzed data from June 2022 to March 2023. Maternal serum samples were collected during routine maternity clinic follow-up visits from 6 to 27 weeks gestation (mean 11.3 weeks), and researchers used these to analyze maternal 25(OH)D (25-hydroxy vitamin D) concentrations. 

The population of this long-term follow-up study consisted of 346 children whose parents completed the Child Behavior Checklist (CBCL) questionnaire (63.4% of those in the follow-up study). Of the original 400-IU group, 169 children (34.6%) were included, and of the original 1,200-IU group, 177 children (36.4%) were included.

The children whose parents completed the CBCL had somewhat more beneficial baseline characteristics regarding breastfeeding duration, maternal 25(OH)D level, smoking status, and parental level compared with nonparticipants.

Intervention

Researchers randomized 169 infants to receive 400 IU and 177 infants to receive 1,200 IU of oral vitamin D3 supplementation daily from ages 2 weeks to 24 months. Supplements were prepared by Orion Pharmaceuticals, and both groups received 5 drops daily. 

Study Parameters Assessed

Researchers assessed childhood psychiatric symptoms at a mean age of 7.1 years for internalizing, externalizing, and total problem scores from the parent-reported Child Behavior Checklist questionnaire.

Primary Outcome

Primary outcomes were internalizing, externalizing, and total problems scores, with clinically significant problems defined as t scores of 64 or greater in the CBCL.

Key Findings

Clinically significant internalizing problems occurred in 10 participants in the 1,200-IU group (5.6% prevalence) compared with 20 participants (11.8%) in the 400-IU group (odds ratio 0.40; 95% CI, 0.17–0.94; P=0.04) after adjustment for sex, birth season, maternal depressive symptoms at birth, and parental single status at follow-up. 

In a post hoc subgroup analysis, 48 children in the 400-IU group with maternal 25(OH)D concentrations less than 30 ng/mL had higher scores for internalizing problems compared with children in the 1,200-IU group, including 44 children with maternal 25(OH)D concentrations below 30 ng/mL (adjusted mean difference 0.49; 95% CI, 0.09–0.89; P=0.02) and 91 children with maternal concentrations above 30 ng/mL (adjusted mean difference 0.37; 95% CI, 0.03–0.72; P=0.04). No differences were found between groups in total or externalizing problems.

Transparency

Eero Kajantie reported receiving grants from the Novo Nordisk Foundation outside the submitted work. This work was supported by the Academy of Finland, Sigrid Jusélius Foundation, Signe and Ane Gyllenberg Foundation, Finland Foundation for Pediatric Research, Yrjö Jahnsson Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Finland Special Governmental Subsidy for Clinical Research, Juho Vainio Foundation, and Päivikki and Sakari Sohlberg Foundation. The authors acknowledge Orion Pharmaceuticals for providing vitamin D3 supplements for the study.

Practice Implications & Limitations

While previous studies1-4 have suggested that higher vitamin D levels during gestation and early childhood may be associated with lower risk of childhood psychopathology, this is the first RCT to assess the potential impact of high-dose vs standard-dose vitamin D supplementation in healthy infants up to age 2 years on psychiatric symptoms in early school age. The authors note that their previous 2021 study5 found no evidence of systematic benefits in child neurodevelopment in the higher-than-standard supplementation group. Furthermore, that 2021 study could not rule out a potentially concerning increase in externalizing problems among children in the higher-supplementation group. This 2023 study under review6 did not find any difference in externalizing differences between groups but found a difference in internalizing behaviors.

Findings from this study support 2 previous studies3,4 suggesting an inverse association between childhood vitamin D levels and depressive symptoms (internalizing behavior); however, one previous study7 showed no association. 

Similarly, studies focusing on maternal pregnancy 25(OH)D levels8-10 have reported inconsistent findings. 

Potential adverse effects of high concentrations of vitamin D should not be ignored.

The subgroup analysis from this study—which may suggest that exposure to lower maternal 25(OH)D levels during pregnancy combined with standard-dose vitamin supplementation could increase the risk for later internalizing problems compared with receiving higher-dose supplementation—should be interpreted cautiously given the absence of interactions between maternal 25(OH)D level and supplementation status.

The strengths of this study include the double-blind RCT design, standardized data collection, well-characterized study population, and validated questionnaire. Limitations include the smaller number of families (n=346) who remained in follow-up and completed the CBCL questionnaire compared to the original study population (N=987). The fact that the study population possessed more beneficial characteristics compared to those lost to follow-up and the proportion of children with lower maternal vitamin D levels was lower among study participants limits the generalizability of the findings. The authors also note that since 2003, milk products and fat spreads in Finland have been fortified with vitamin D, resulting in improved population vitamin D levels; therefore, transferability of findings to countries lacking vitamin D fortification and to children living at other geographical latitudes remains hypothetical pending future research.

A meta-analysis and systematic review found that high-dose vitamin D supplementation was not associated with an increased risk of serious adverse events in children aged 0 to 6 years and that clinical adverse events potentially related to the supplementation were rare.11 However, the potential adverse effects of high vitamin D concentrations should not be ignored. 

Studies have associated higher-dose vitamin D supplementation in infancy with increased risk of milk allergy in infants, as well as an increased risk of allergic sensitization in infants with high cord-blood vitamin D status.12 A study looking at maternal vitamin D levels and early growth indicated that toddlers born to mothers with pregnancy 25(OH)D greater than 125 nmol/L were, at age 2 years, lighter and thinner than the reference group with a 25(OH)D of 50 to 74.9 nmol/L (P<0.010).13 Nephrocalcinosis has also been seen in children who received high-dose vitamin D, with children of smaller body surface area particularly vulnerable.14 

If health practitioners are giving high-dose vitamin D to patients on a long-term basis regardless of reason, it seems prudent to follow the recommendation of the Drugs and Therapeutics Committee of the Pediatric Endocrine Society to obtain serum 25(OH)D levels in infants and children who receive long-term vitamin D supplementation at or above the recommended upper intake level.15

While this secondary analysis of an RCT found that a higher-than-standard vitamin D3 supplementation (1,200 IU daily vs 400 IU) between ages 2 weeks and 2 years reduced the risk of internalizing problems later in childhood at ages 6 to 8 years, in light of potential adverse effects of high-dose vitamin supplementation (allergies, growth inhibition), findings need to be repeated and assessed for general safety. Even if minimal, the potential nonbeneficial effects of higher-than-standard doses warrant further studies in which both safety and benefits should be evaluated before making any conclusions regarding population-level practice implications. 

The study adds to the body of evidence suggesting vitamin D’s potential role in several outcomes, including bone health,16,17 immune health,18 and potentially mental wellness. Pediatricians and other healthcare providers should have a low threshold for screening those at higher risk for vitamin D deficiency, as the benefits of repleting deficient states is not controversial.19 Children at risk include those on anticonvulsants or glucocorticoids, children with chronic disease associated with malabsorption such as cystic fibrosis or inflammatory bowel disease, and children with frequent fractures or low bone mineral density, or children with nonspecific symptoms such as poor growth, gross motor delays, and unusual irritability. Other risk factors include maternal vitamin D deficiency, low intake of fortified food, breastfeeding, low compliance of supplementation, dark skin, inadequate sun exposure, premature birth, overweight, and living at high latitude. With respect to environmental variations, the Canadian Pediatric Society recommends 800 IU/day for breastfed infants during the winter months.20 

What is most concerning from a public health perspective is a 2020 study21 that found that, during the first 8 years after the guideline release recommending a doubling of the intake from 200 to 400 IU/day, there was no improvement in the rates of meeting the 2008 American Academy of Pediatrics (AAP) vitamin D intake guidelines (400 IU/day) for infants. Additionally, although <40% of infants met guidelines in nearly all demographic subgroups, among breastfeeding infants, lower socioeconomic status was associated with increased risk of failing to meet the vitamin D intake guidelines. These findings suggest that renewed consideration of how to best meet even the recommended vitamin D supplement guidelines is warranted. The potential mental health implications suggested in this study validate the importance for pediatricians and health care providers to continue educating all parents and caregivers about the importance of vitamin D supplementation.

Let’s redouble our efforts to make sure our patients are meeting the recommended vitamin D guidelines while we await future research on the risks and benefits of higher-dose supplementation.

Categorized Under

Michelle Loy

MD, FAAP

Michelle Loy, MD, FAAP, is a nationally recognized, quadruple board-certified physician who received her undergraduate degree from Harvard College, her doctorate in medicine from Weill Cornell Medical College, her pediatrics residency training from New York Presbyterian Hospital–Cornell, and her integrative medicine fellowship training from Columbia University/Stamford Hospital. She utilizes evidence-based interventions from both modern medicine and time-tested traditional modalities including nutrition, movement, acupuncture, botanicals, and mind-body medicine to prevent and manage chronic medical conditions across all age groups at Integrative Health and Well-Being-Weill Cornell Medicine/NY Presbyterian.

References

  1. Föcker M, Antel J, Ring S, et al. Vitamin D and mental health in children and adolescents. Eur Child Adolesc Psychiatry. 2017;26(9):1043-1066.
  2. Khoshbakht Y, Bidaki R, Salehi-Abargouei A. Vitamin d status and attention deficit hyperactivity disorder: a systematic review and meta-analysis of observational studies. Adv Nutr. 2018;9(1):9-20.
  3. Tolppanen AM, Sayers A, Fraser WD, Lewis G, Zammit S, Lawlor DA. The association of serum 25-hydroxyvitamin D3 and D2 with depressive symptoms in childhood--a prospective cohort study. J Child Psychol Psychiatry. 2012;53(7):757-766.
  4. Robinson SL, Marín C, Oliveros H, Mora-Plazas M, Lozoff B, Villamor E. Vitamin D deficiency in middle childhood is related to behavior problems in adolescence. J Nutr. 2020;150(1):140-148.
  5. Tuovinen S, Räikkönen K, Holmlund-Suila E, et al. Effect of high-dose vs standard-dose vitamin d supplementation on neurodevelopment of healthy term infants: a randomized clinical trial. JAMA Netw Open. 2021;4(9):e2124493.
  6. Sandboge S, Räikkönen K, Lahti-Pulkkinen M, et al. Effect of vitamin D3 supplementation in the first 2 years of life on psychiatric symptoms at ages 6 to 8 years: a randomized clinical trial. JAMA Netw Open. 2023;6(5):e2314319.
  7. Al-Sabah R, Al-Taiar A, Shaban L, Albatineh AN, Sharaf Alddin R, Durgampudi PK. Vitamin D level in relation to depression symptoms during adolescence. Child Adolesc Psychiatry Ment Health. 2022;16(1):53.
  8. Daraki V, Roumeliotaki T, Koutra K, et al. High maternal vitamin D levels in early pregnancy may protect against behavioral difficulties at preschool age: the Rhea mother-child cohort, Crete, Greece. Eur Child Adolesc Psychiatry. 2018;27(1):79-88.
  9. Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Kusel MM, Hart PH. Maternal serum vitamin D levels during pregnancy and offspring neurocognitive development. Pediatrics. 2012;129(3):485-493.
  10. Sammallahti S, Holmlund-Suila E, Zou R, et al. Prenatal maternal and cord blood vitamin D concentrations and negative affectivity in infancy. Eur Child Adolesc Psychiatry. 2023;32(4):601-609.
  11. Brustad N, Yousef S, Stokholm J, Bønnelykke K, Bisgaard H, Chawes BL. Safety of high-dose vitamin D supplementation among children aged 0 to 6 years: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(4):e227410.
  12. Rosendahl J, Pelkonen AS, Helve O, et al. High-dose vitamin D supplementation does not prevent allergic sensitization of infants. J Pediatr. 2019;209:139-145.e1.
  13. Hauta-Alus HH, Holmlund-Suila EM, Kajantie E, et al. The effects of vitamin D supplementation during infancy on growth during the first 2 years of life. J Clin Endocrinol Metab. 2021;106(3):e1140-e1155.
  14. Lin TH, Lu HJ, Lin CH, et al. Nephrocalcinosis in children who received high-dose vitamin D. Pediatr Nephrol. 2022;37(10):2471-2478.
  15. Vogiatzi MG, Jacobson-Dickman E, DeBoer MD. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014;99(4):1132-1141.

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