Study selection

Initially, 10 690 articles were identified. Title and abstract screening returned 298 potential articles. After full-text review, 274 articles were excluded, and 24 intervention studies (including 2 with behavioural components) were included. No further behavioural studies were identified from the updated literature search in November 2020 (see Fig. 1).

Fig. 1

Study flow diagram. RCT, randomised controlled trial

Study characteristics

The majority^{(Reference Callaghan, Moy and Booth11)} of studies included were conducted in the USA, with two further studies each in Australia, Canada, and Mongolia. One study was undertaken in each of the following: UK, Norway, Denmark, Pakistan, India, Nigeria, and Turkey. Table 1 summarises these papers.

Table 1

Studies included in systematic review

RCT, randomised controlled trial; SCD, sickle cell disease; UHT, ultra-high-temperature.

*Serum/plasma concentration of 25-hydroxyvitamin-D (25(OH)D), the major circulating metabolite of vitamin D, is expressed as nanomoles per litre (nmol/l) or nanograms per millilitre (ng/ml); 2·5 nmol/l is equivalent to 1 ng/ml. Due to differences in molecular mass and the amount required to prevent rickets, there is no absolute agreement on conversion of ng to nmol for 25(OH)D₂ and 25(OH)D₃. Inconsistencies relating to these measurements need consideration when interpreting studies comparing vitamin D₂ and D₃⁽⁷⁰⁾.

With reference to quality appraisal, nineteen studies were appraised using Cochrane Risk of Bias for RCT. Of these, one^{(Reference Abrams, Hawthorne and Chen36)} had a low risk of bias and the remaining eighteen had some concerns. One study^{(Reference Green, Li and Barr37)}, appraised with the ROBINS-I tool, was coded as having a critical risk of bias due to confounding. Of the NHLBI appraised studies, two were rated as fair^{(Reference Mutlu, Kusdal and Ozsu38,Reference Ganmaa, Drs and Frazier39)} and two as good^{(Reference Rajakumar, Fernstrom and Holick40,Reference Rajakumar, Fernstrom and Janosky41)} (see Tables 2–5).

Table 2

Cochrane risk of bias for randomised controlled trials (RCT)^{(Reference Sterne, Savović and Page31)}

Table 3

Cochrane ROBINS-I^{(Reference Sterne, Hernán and Reeves32)}

Table 4

Quality assessment tool for observational cohort and cross-sectional studies⁽³³⁾

Table 5

Quality assessment tool for before-after (pre-post) studies with no control group⁽³³⁾

Behavioural interventions

All studies included conducted a vitamin D pharmacological supplementation intervention in our target population, with two that incorporated a behavioural component to their intervention strategy^{(Reference Mutlu, Kusdal and Ozsu38,Reference Madar, Klepp and Meyer42)} in addition to the pharmacological intervention. We found no study that explicitly defined a primary aim of evaluating a behavioural intervention undertaken with the intention to study its effect on vitamin D supplement uptake.

Madar et al. ^{(Reference Madar, Klepp and Meyer42)} (Table 2; overall risk of bias: some concerns) studied the effect of vitamin D₂ drops on serum 25-hydroxy-vitamin D (25(OH)D) in infants with immigrant origin within a cluster RCT. In total, sixty-six healthy infants of Pakistani (South Asian origin), Turkish (West Asian/Middle Eastern) or Somali (East African) origin were recruited for the study from eight child health clinics in Oslo, Norway. The behavioural component involved multilingual translated brochures for mothers, with information provided to each ethnic group on vitamin D, its sources and instructions on how to administer the vitamin D drops, made available free of charge. Aims were to evaluate whether a free supply of a 400 iu daily dose, for 6-week old infants, together with information handouts that had been translated into Urdu, Turkish or Somali languages incorporating text and simple illustrations, improved vitamin D status, assessed at 7-week follow-up in the intervention and control group. Fifty-one (78 %) infants completed the study, with serum 25(OH)D levels significantly higher in the intervention group v. Control group (93·5 v. 72·7 nmol/l; P = 0·03). Amongst exclusively breast-fed infants at baseline, serum 25(OH)D levels increased by 32·3 nmol (P = 0·035) in the intervention group. This study concluded^{(Reference Madar, Klepp and Meyer42)} that free supply of vitamin D drops, with translated information handouts, significantly improved the vitamin D status of healthy infants of immigrant background. Considering the Behaviour Change Wheel framework, this combined intervention strategy (if part of an explicitly stated behavioural intervention) could have been coded under criteria; education and training (translated information leaflets; administration advice) and enablement (free supply)^{(Reference Michie, van Stralen and West30)}.

The second study with behavioural components centred around a nationwide prevention campaign instigated due to resurgence of vitamin D deficiency rickets in children of ethnic minority origin living in Turkey, a sunny country in West Asia/Middle East. In order to gauge the campaign’s impact which included supply of vitamin D supplements as an intervention, Mutlu et al. ^{(Reference Mutlu, Kusdal and Ozsu38)} (Table 4; overall risk of bias: Fair) report from evaluation undertaken with a small sample of 85 healthy infants (45 girls and 40 boys; individual ethnic origin data not provided). The over-arching aims for the campaign, which also incorporated a curriculum to train healthcare workers, were to encourage the entire population, and especially pregnant and nursing women and infants, to have adequate sunlight exposure. Distribution of vitamin D supplements to every newborn at no cost to families was made through Turkey’s network of primary care units and maternal health centres. The study had limitations; no control group, high risk of bias from confounding and no statistical test was performed (Table 4). Evaluation was by way of face-to-face interviews with the mothers, advised to administer three drops (400 iu) daily. Overall, seventy-six (89 %) infants received the vitamin D dose recommended. However, mothers for twenty-six (31 %) infants stated that they did not administer the dose on a daily basis. The research team concluded that for prevention of vitamin D deficiency in infants, a daily dose of 400 iu was sufficient. Considering the Behaviour Change Wheel framework, the intervention strategy utilised could be coded under criteria of education and enablement^{(Reference Michie, van Stralen and West30)}. The authors^{(Reference Mutlu, Kusdal and Ozsu38)} noted that the major obstacles for use of vitamin D supplements in Turkey included limited public awareness, access to healthcare and supplement costs.

Pharmacological interventions

All studies included in this review incorporated some form of pharmacological intervention, the results of which are summarised in the following sections. Ten studies^{(Reference Yu, Sykes and Sethi7,Reference Green, Li and Barr37,Reference Mutlu, Kusdal and Ozsu38,Reference Madar, Klepp and Meyer42–Reference Hollis, Johnson and Hulsey48)} were undertaken during the pregnancy/newborn phase with ethnic minority origin as a main risk factor. One study specifically targeted a cohort with known ‘at-risk status’, that is, nutritional rickets^{(Reference Mondal, Seth and Marwaha44)}.

Pregnancy/newborn group

Green et al.’s^{(Reference Green, Li and Barr37)} observational study assessed sixty-five Canadian breast-fed infants (Asian/White; aged 0·2–0·4 weeks), noting that supplementation with 10 mcg vitamin D helped infants achieve significantly higher 25(OH)D concentrations compared with those who received less (mean 25(OH)D 9·4 ng/ml higher; P = 0·003). Maternal vitamin 25(OH)D levels, season, skin colour and ethnicity were not significant determinants of infant vitamin 25(OH)D levels. Hanson et al.’s study^{(Reference Hanson, Armas and Lyden46)} also undertaken in Canada evaluated newborn infants receiving formula feeds during intensive care hospitalisation. Classified as White or non-White African American origin, the study arms included supplementation with 400 iu vitamin D or matching placebo with formula feeds. White infants achieved significantly higher mean 25(OH)D levels by time of discharge (P = 0·0003).

Hollis et al. reported findings from two studies^{(Reference Hollis, Wagner and Howard43,Reference Hollis, Johnson and Hulsey48)} . The 2011 US cohort^{(Reference Hollis, Johnson and Hulsey48)} were women with singleton pregnancies, given varying doses of vitamin D (400/2000/4000 iu daily) from 12–16 weeks of gestation to delivery. The 4000 iu daily dose was safe and the most effective in achieving sufficiency in all women regardless of race (Caucasian; African American; Hispanic; P < 0·0001). The 2015 US study^{(Reference Hollis, Wagner and Howard43)} included 334 mother–infant pairs with newborns of 4–6 weeks old, recruited as mothers planned to breast-feed for 6 months. Compared to a 400 iu daily dose, the higher 6400 iu daily dose showed a significant increase in maternal vitamin D levels (P < 0·0001) and was safe. Vitamin D deficiency in breast-fed infants was affected by race, with African American mothers and infants having substantially lower circulating 25(OH)D levels.

Rodda et al.’s Australian study^{(Reference Rodda, Benson and Vincent45)} recruited 78 ethnic minority pregnant women and newborns, identified on the basis of dark skin or veiling (84 % treated and 97 % control group). They were supplemented with 2000–4000 iu daily from 12 to 16 weeks’ gestation to delivery. Umbilical cord serum 25(OH)D levels at delivery were higher in neonates of mothers in the treated group (81 nmol/l v. 42 nmol/l; P < 0·0001).

Yu et al.’s prospective UK study^{(Reference Yu, Sykes and Sethi7)} recruited 180 women, of Indian Asian, Middle Eastern, Black and Caucasian origin, treated from 27 weeks’ gestation to delivery. Study arms compared a single 200 000 iu dose injection, an 800 iu daily dose and no treatment. Treated mothers had significantly improved vitamin D levels (42 v. 27 nmol/l; P < 0·0001), but only a small percentage (women 30 %; babies 8 %) given supplements achieved sufficiency levels (50 nmol/l or over).

The intervention in Hossain et al.’s single-centre open-label RCT^{(Reference Hossain, Kanani and Ramzan47)} in Pakistan (South Asia) was 4000 iu vitamin D taken daily from gestational week 20 to delivery. Positive correlation was found between maternal and neonatal 25(OH)D levels (r = 0·83; P = 0·001), with improved status with supplementation (maternal 25(OH)D increased from mean 8·82 ng/dl to 18·3 ng/dl; P = 0·001). Mondal et al. ^{(Reference Mondal, Seth and Marwaha44)} studied seventy-one Indian children (South Asia) with nutritional rickets, aged between 6 months and 5 years, given either a single intramuscular dose of 600 000 iu vitamin D or 10 weeks of a 60 000 iu dose taken weekly. Both were safe and effective with no difference found in efficacy on comparing diagnostic parameters for rickets (P > 0·05).

The Madar et al. ^{(Reference Madar, Klepp and Meyer42)} and Mutlu et al. ^{(Reference Mutlu, Kusdal and Ozsu38)} studies discussed above included a behavioural component in addition to the pharmacological intervention.

Children

Mondal et al.’s^{(Reference Mondal, Seth and Marwaha44)} study on children aged between 0·5 and 5 years is discussed above. Of fourteen further papers in children (aged 1–20 years), ten were undertaken in the USA and included African American^{(Reference Rajakumar, Fernstrom and Holick40,Reference Rajakumar, Fernstrom and Janosky41,Reference Rajakumar, Moore and Yabes49–Reference Rajakumar, Moore and Yabes52)} , Hispanic, Asian and White^{(Reference Abrams, Hawthorne and Chen36)}, or Black and White^{(Reference Sacheck, Van Rompay and Chomitz53–Reference Talib, Ponnapakkam and Gensure55)} children. None reported including any type of behavioural intervention.

Lewis et al. ^{(Reference Lewis, Laing and Hill Gallant54)} assessed five daily oral vitamin D doses (0,400,1000,2000 and 4000 iu) in Black and White children aged 9–13 years. Increases in vitamin 25(OH)D levels depended on dose taken; 12-week changes ranged between −10 and 76 nmol/l (placebo v. 4000 iu, respectively). In the highest dose group, larger vitamin D gains were seen in White compared with Black children (P < 0·01)

Rajakumar et al. reported vitamin D insufficiency at baseline^{(Reference Rajakumar, Fernstrom and Janosky41)} in about half of their study group (6–10 years old, African American children). Using the 2005 definition for adults, deficiency status was defined as less than 10 ng/ml and insufficiency as between 10 and 20 ng/ml^{(Reference Rajakumar, Fernstrom and Janosky41)}. Supplementation with 400 iu daily for 4 weeks helped achieve a significant increase in levels (see Table 1), but insufficiency status still persisted in 18 % of the experimental group^{(Reference Rajakumar, Fernstrom and Janosky41)}. In a separate study, Rajakumar et al. also noted^{(Reference Rajakumar, Fernstrom and Holick40)} that vitamin D deficiency is common amongst obese and non-obese preadolescent African American children, finding that 400 iu daily dose was not enough to raise vitamin D serum levels to 30 ng/ml (Table 1; deficiency defined as less than 20 ng/ml; insufficiency 21–29 ng/ml). In further work^{(Reference Rajakumar, Moore and Yabes49,Reference Rajakumar, Moore and Yabes52)} , Rajakumar et al. studied African American and White children aged 8–14 years supplemented with vitamin D₃ 1000 iu/d for 6 months. They reported that vitamin D₃ supplementation varied with race and was more effective and significant in Black children^{(Reference Rajakumar, Moore and Yabes49)} (Table 1). In addition, the intake required to maintain concentrations at 20 ng/ml in 97·5 % of Black and White children, adjusting for race and pubertal status, was three times higher than the US recommended allowance of 600 iu/d^{(Reference Rajakumar, Moore and Yabes52)}. Sachek et al.’s^{(Reference Sacheck, Van Rompay and Chomitz53)} randomised control trial recruited 604 children (Black, Hispanic, White and Asian), aged 8–15 years. They found that serum vitamin D levels increased over 6 months with all dose ranges (600, 1000 or 2000 iu daily) with the 2000 iu daily dose achieving a higher vitamin D concentration compared with the two lower doses (33·1 v. 26·3 and 27·5 ng/ml; P < 0·001). Talib et al. ^{(Reference Talib, Ponnapakkam and Gensure55)} found that adolescents (Hispanic, Black, White and Asian; 13–20 years old) required 8 weeks of high-dose colecalciferol, of at least 5000 iu/d in order to correct deficiency status, noting also that obese adolescents had poorer response to treatment (13·7 +/− 10·7 v. 21·9 +/− 16·9 ng/ml; P < 0·001).

Abrams et al. ^{(Reference Abrams, Hawthorne and Chen36)} found no significant effect of an increase in vitamin D3, with decrease in parathyroid hormone levels, on calcium absorption, which was one of their study’s primary outcomes of interest. The pharmacological intervention used was supplementation with 1000 iu daily vitamin D for 8 weeks in African American, Hispanic, Asian, and White children aged between 4 and 9 years. Dong et al. ^{(Reference Dong, Stallmann-Jorgensen and Pollock50)} studied supplementation in forty-nine healthy African American children, aged 14–18 years, with 2000 iu/d v. 400 iu/d in the control group. They reported the 2000 iu daily dose as probably more effective (see Table 1) in optimising vitamin D status and counteracting progression of aortic stiffness in Black youth.

Doherty et al.’s^{(Reference Dougherty, Bertolaso and Schall51)} target group were African American children and young adults (5–20 years old) with or without sickle cell disease (SCD-SS). The study aim was to assess safety and efficacy of two oral vitamin D₃ daily doses (4000 iu and 7000 iu). They noted that with 12 weeks of supplementation, both doses were safe and well tolerated but deficiency status (<20 ng/ml) was eliminated only in those receiving 7000 iu/d (P < 0·05).

Andersen et al. ^{(Reference Andersen, Molgaard and Skovgaard56)} recruited adolescent girls of Pakistani (South Asia) origin living in Denmark, aged 10–15 years, to study two vitamin D doses (10, 20 mcg/d). It is difficult to comment on any significant difference in 25(OH)D levels in the group after 1 year, as numbers recruited were small (n 21). Ganmaa et al. ^{(Reference Ganmaa, Drs and Frazier39,Reference Ganmaa, Stuart and Sumberzul57)} found that drinking ultra-high-temperature (UHT) processed milk fortified with about 100 iu vitamin D per serving improved levels in Mongolian (East Asia) children aged 9–11 years, and that correction of baseline deficiency in Mongolian children aged 12–15 years with 800 iu daily over 6 months increased growth^{(Reference Ganmaa, Stuart and Sumberzul57)}. Thatcher et al. ^{(Reference Thacher, Fischer and Pettifor58)} studied Nigerian (West Africa) children aged between 1 and 14 years with nutritional rickets, finding that calcium supplementation with or without vitamin D was more effective then vitamin D alone in healing active rickets (P < 0·001). (Tables 1, 6 and 7).

Table 6

Pharmacological vitamin D doses used in the trials included in systematic review and intervention outcome

Table 7

Vitamin D intervention study in healthy v. at-risk population as defined by research group

Research published after completion of the initial review

The updated literature review on MEDLINE, EMBASE, CINAHL and Cochrane Library databases, including secondary search of Google Scholar, undertaken for February 2018–November 2020, focused purely on identifying behavioural intervention studies. No publication with an explicitly defined behavioural intervention implemented to study vitamin D supplementation outcomes was identified (see Fig. 1). Protocols for two new systematic reviews have been published^{(Reference Yousef, Elliot and Manuel66,Reference Best, Xu and Patchen67)} , but there is no indication that any behavioural interventions per se will be considered.