Research in vitamin D and its function resulted in numerous position statements and guidelines for vitamin D supplementation. Historically supplementation was based on the vitamin D content of a teaspoon of cod liver oil, equalling approximately 400 International Units (IU) . Current recommendations from public health authorities range from 400 to 800 IU per day in infants , , , . Surrounding factors like diet, season and latitude significantly impact on vitamin D levels . Risk factors for vitamin D deficiency include dark skin, cultural factors like veiling and lack of sun exposure .
Vitamin D deficiency leads to impaired bone health and there is increasing evidence that extra skeletal functions like support of the immune system and cancer-prevention are negatively affected as well .
Some public health initiatives recommended prophylactic vitamin D supplementation without initial testing of baseline 25 hydroxyvitamin D [25(OH)D] levels, for example, in Germany and Scandinavia . This is controversial for sunny countries like Spain or Australia , . It is recommended to monitor 25(OH)D levels before starting vitamin D supplementation at doses higher than the recommended upper intake level for a longer period of time .
There is a lack of studies looking at the practical consequences of such initiatives. Until 1989 regular preventative examinations of children in former East Germany were regulated and standardised by official directives and guidelines . These comprised neurodevelopmental assessment, vaccination and general advice including supplementation with vitamin D . Outcomes and findings from these examinations were documented in great detail and included adherence to vitamin D prophylaxis.
We had the opportunity to access data from this period and initiated the presented study to  analyse the impact of a nationwide guideline for universal vitamin D supplementation on clinical and biochemical parameters during the first year of life and  evaluate the impact of surrounding factors.
Patients and methods
As part of a public health initiative in East Germany in 1989, vitamin D prophylaxis with 400 IU daily of oral vitamin D3 was offered to families after delivery for every infant starting from day 15 until 12 months of age , . A field-study of paediatric outpatient clinics was conducted in cities at different latitudes to evaluate this approach. Focussing on signs of vitamin D deficiency the consultations were standardised , : a history was taken, patients were clinically examined, their nutrition was reviewed and blood analyses were initiated, adherence to vitamin D prophylaxis was documented. Regular visits were scheduled at monthly intervals during the first 6 months and 6 weekly from 7 to 12 months of life. Parents of participants gave written informed consent that clinical and biochemical data could be used for analysis and publication. These data were analysed retrospectively.
The following clinical and biochemical outcome measures were analysed:
- Clinical signs of vitamin D deficiencyAt each clinic visit participants were examined by experienced paediatricians to look for craniotabes, widened epiphyses, deformities of the legs and spine and rachitic rosary, muscle weakness, changes in abdominal muscle tone and sweating.
- Biochemical parameters of vitamin D and calcium metabolism25(OH)D, calcium, phosphate and ALP were included if available. The vitamin D analysis was based on a 25(OH)D radioimmunoassay using the micromethod by Aksnes . Addition of a protein fraction obtained by gel filtration of human serum, shown to bind only vitamin D, enhanced the specificity and reproducibility of the assay without interfering with the binding properties of 25(OH)D. Serum samples were extracted by chloroform-methanol. The assay has a detection limit of 0.4 nmol/L in serum, and an intra- and inter-assay coefficient of variation of 6.8 and 8.1%, respectively. Standard assays were used for calcium, phosphate and ALP .
- Surrounding factorsFollowing dietary recommendations children were either breastfed or on vitamin D-free formula with solids introduced from 6 months of age. Diet was assessed using questionnaires.
Participating centres were chosen to represent a North-South gradient. Data on duration of sunshine were provided from the German Bureau of Meteorology.
The preparation used for vitamin D supplementation was Dekristol® (Mibe GmbH, Brehna, Germany), which contains 400 IU of vitamin D3 in tablet form. Families were instructed to dissolve the tablets in a spoon of milk for infants. Tablets were not to be part of a regular meal as this would negatively affect resorption. The tablet could be administered directly to children from 8 months of age. Tablets also consisted of lactose-monohydrate, kristalline cellulose, starch, sucrose, silicumdioxide, magnesiumstearate, sodiumascorbate, medium-chain triglycerides and all-rac-alpha tocopherol.
This is a cross-sectional analysis in monthly intervals from 1 to 12 months of age. Power calculation was based on the number of subjects (n=8) needed to detect a change of 5 nmol/L in 25(OH)D levels with power set at 0.8 and alpha of 0.05. A generalised linear model was used to analyse differences between timepoints and the impact of surrounding factors: nutrition, latitude and season. Significance was set at p<0.05. Correlations were analysed using linear regression models; 25(OHD) levels and ALP were assessed with partial correlation analysis (SPSS statistics, version 22, IBM Corporation, Armonk, NY, USA, 2013).
Data from 3481 newborns and infants were included from centres in (North to South): Ribnitz-Damgarten (54.1°N, 12.3°E), Wismar (53.9°N, 11.5°E), Berlin (52.5°N, 13.4°E), Dessau (51.8°N, 12.3°E), Halle (51.5°N, 11.9°E), Görlitz (51.1°N, 14.6°E) and Jena (50.6°N, 11.4°E). Clinical information could be included for all participants, biochemical data were available for 776 of them. These findings were grouped by age. Looking at individual centres there were no biochemical data from Görlitz; calcium, phosphate and ALP were analysed in Wismar, Berlin and Dessau; calcium, phosphate, ALP and 25(OH)D could be included from Ribnitz-Damgarten, Halle and Jena. Some participants had multiple blood tests. The study in Halle was conceptualised as a longitudinal study. However, missing data did not allow a longitudinal analysis (Figure 1) and results were included in the cross-sectional analysis. From individual blood samples different combinations of parameters were analysed as specified in Figure 2. This reflects clinical practice as sometimes due to small specimen size the volume was not sufficient to analyse the full set of parameters. Some children underwent a maximum of two venipunctures per visit to obtain a maximum volume of blood to allow the analysis of as many parameters as possible.
Out of the 3481 participants, 41 showed craniotabes (1.17%). There were no other clinical signs of rickets. From the cohort in Halle biochemical data were available from 14 participants with craniotabes at 1–7 months of age. Twelve of those analyses were taken between November and January (autumn and winter), two in June (summer). These participants were vitamin D sufficient. Levels (minimum–maximum) ranged as follows: 25(OH)D 62–263 nmol/L, ALP 531–1458 U/L, calcium 2.12–2.77 mmol/L. Four subjects were breastfed, five on formula and five on formula and solids.
25(OH)D levels (mean and SEM, total analyses n=572) after birth (n=28) were 36(7) nmol/L, increased to 64(4) nmol/L at 1 month of life (n=70, p<0.0001), 91(5) nmol/L at 3 months (n=95, p<0.0001), stabilised until 6 months, decreased to 65(8) nmol/L at 8 months (n=21, p=0.005) and then ranged between 33 and 109 nmol/L until 12 months. Maximum level was 289 nmol/L without evidence of vitamin D intoxication (Table 1).
25(OH)D, calcium, phosphate and ALP during the first year of life by age groups.
|25(OH)D, nmol/L, mean (SE)||36 (7)||63 (4)a||91 (5)a||98 (4)||91 (5)||100 (6)||89 (4)||75 (6)||65 (8)||78 (5)||72 (19)||78 (8)||90||79 (2)|
|95% confidence interval||23–49||55–71||81–101||91–105||82–100||89–112||81–98||62–88||50–80||68–88||33–111||62–94||72–109||75–83|
|Number of observations||28||70||45||95||57||35||65||29||21||48||3||18||13||527|
|Number (%) <30 nmol/L||12 (43)||7 (10)||2 (4)||1 (1)||1 (2)||0||0||1 (3)||4 (19)||0||0||0||0||28 (5)|
|Number (%) 30–50 nmol/L||10 (36)||15 (21)||4 (9)||3 (3)||5 (9)||5 (14)||3 (5)||3 (10)||2 (10)||8 (17)||1 (33)||1 (6)||0||60 (11)|
|Number (%) 51–75 nmol/L||2 (7)||28 (40)||9 (20)||16 (17)||14 (15)||4 (11)||16 (25)||14 (49)||5 (20)||13 (27)||0||7 (40)||4 (31)||132 (25.5)|
|Number (%) 76–250 nmol/L||4 (14)||20 (29)||29 (65)||74 (78)||37 (65)||25 (73)||46 (70)||11 (38)||10 (51)||27 (56)||2 (67)||10 (54)||9 (69)||304 (58)|
|Number (%) >250 nmol/L||0||0||1 (2)||1 (1)||0||1 (2)||0||0||0||0||0||0||0||3 (0.5)|
|Calcium, mmol/L, mean (SE)||2.43 (0.04)||2.54 (0.03)a||2.54 (0.03)||2.53 (0.02)||2.54 (0.03)||2.49 (0.03)||2.52 (0.02)||2.49 (0.04)||2.5 (0.06)||2.46 (0.03)||2.5 (0.07)||2.5 (0.06)||2.5 (0.04)||2.5 (0.01)|
|95% confidence interval||1.83–2.89||1.9–3.8||2.05–3.15||1.97–3||2.2–3.21||2.14–3.03||2.0–3.0||2.23–2.98||2.2–2.9||2.11–2.86||2.38–2.66||2.37–2.7||2.08–2.8||1.83–3.21|
|Number of observations||31||63||52||139||73||47||89||33||15||59||9||12||27||649|
|Phosphate, mmol/L, mean (SE)||2.05 (0.08)||2.18 (0.05)||2.24 (0.06)||2.21 (0.34)||2.22 (0.05)||2.17 (0.06)||2.22 (0.04)||2.32 (0.07)||2.04 (0.01)||2.02 (0.05)||2.13 (0.13)||1.98 (0.12)||1.88 (0.08)||2.12 (0.02)|
|95% confidence interval||1.12–2.87||1.47–3.25||1.64–3.19||1.31–3.65||1.35–4.14||1.35–3.06||1.31–3.74||1.55–3.22||1.6–2.61||1.22–2.93||1.74–2.75||1.68–2.31||1.36–2.89||1.12–4.14|
|Number of observations||26||63||48||138||70||40||88||34||16||58||9||11||27||628|
|ALP, U/L, median|
|(Interquartile range)||645 (465)||824 (49)a||724 (305)||708 (294)||672 (342)||540 (214)||614 (40)||570 (204)||492 (212)||546 (284)||558 (159)||658 (341)||561 (305)||642 (295)|
|Number of observations||31||66||50||163||73||38||100||35||16||69||9||12||28||690|
Levels are described as mean, SE and range (minimum–maximum), ALP as median and interquartile range. Analysis between timepoints was performed using a generalised linear model with significance set at p<0.05. aTimepoints of significance.
Calcium levels (n=649, mean and SEM) increased significantly from 2.43(0.04) mmol/L after birth to 2.54(0.03) mmol/L at 1 month of age (p<0.05) and subsequently 2.46–2.54 mmol/L until 12 months of age. Hypercalcaemia (>2SDS=2.95 mmol/L) or hypocalcaemia (<2SDS=2.06 mmol/L) occurred in <0.1% (Table 1). There is no formal grading for hypercalcaemia. In children until 12 months of age 2.7 mmol/L can be considered normal . Applying ranges as suggested by Horwitz , looking at our study cohort n=476 were within normal limits (2.2–2.65 mmol/L). n=119 showed mild hypercalcaemia (2.65–3 mmol/L). Five subjects showed moderate hypercalcaemia (3–3.5 mmol/L), one participant had a calcium level of 3.8 mmol/L (severe hypercalcaemia: >3.5 mmol/L) with a corresponding 25(OH)D level of 51 nmol/L.
Phosphate levels (n=629, mean and SEM) gradually increased from 2.05(0.08) mmol/L at 0.5 months of age to 2.32(0.07) mmol/L at 7 months of age to then slowly decrease to 1.88(0.08) mmol/L at 12 months of age. Phosphate levels were outside the 2SDS-range (1.4–3 mmol/L) in <0.2% (Table 1).
The median level for ALP (n=690, median and interquartile range) was 642 (295) U/L. According to Thomas  the normal range for ALP (U/L) can be specified for age groups. The number of subjects with levels higher than the upper range per age group is described in Table 2. There was a peak at 1 and 2 months of age (n=50, p<0.01), followed by a significant decrease in ALP-levels until 9 months of age and an increase until 12 months of age that was not associated with low 25(OH)D levels. Paired samples for 25(OH)D and ALP were available from 419 tests. The correlation (corrected for age) between 25(OH)D and ALP was low at r=0.117, but significant: p=0.018 (Figure 3).
ALP levels outside the normal range by age groups.
|Normal range per age group||Subjects with levels higher than normal range|
|Age, months||Number of subjects/(total), %|
|Birth–10 days: 110–450 U/L||0–0.5||20/(31), 64|
|11–30 days: 110–580 U/L||0.5–1||45/(66), 68|
|1–6 months: 140–720 U/L||2||33/(50), 66|
|7–12 months: 120–700 U/L||7||8/(35), 22|
Distribution of elevated ALP levels by age groups  shown as numbers/total and percentage of levels measured.
Food diaries were available from 233 participants. Groups and average 25(OH)D levels (mean and SEM) were as follows: breastmilk [n=72, 85(5) nmol/L], vitamin D-free formula [n=100, 80(3) nmol/L], breastmilk and vitamin D free solids [n=12, 49(11) nmol/L] and vitamin D-free formula and -solids [n=107, 79(4) nmol/L]. There was no significant correlation between diet and 25(OH)D levels.
The total yearly sunshine duration was 1628 h in the South (Jena: 50.6°N, 11.4°E) and 1917 h in the North (Ribnitz-Damgarten: 54.1°N, 12.3°E). There was a North-South gradient in 25(OH)D with higher levels (mean and SEM) in the South despite of the longer sunshine duration in the North: Ribnitz-Damgarten 78(3) nmol/L, Halle 83(3) nmol/L, Jena 88(3) nmol/L.
There were seasonal variations in 25(OH)D levels with a rise during spring and autumn (Figure 4).
This is a retrospective analysis of universal vitamin D supplementation in a population-based sample during the first year of life in former East Germany in 1989. Supplementation and sun exposure could be considered as the only sources of vitamin D because participants were either breastfed or on vitamin D free formula with vitamin D free solids added from 6 months of age. Data were collected under everyday clinical conditions and revealed that 400 units of vitamin D3/day provide sufficient 25(OH)D levels. Latitude and season were influencing factors in the regions of Germany that were part of the analysis. Looking at the history of rickets in Germany, between 1901 and 1908 an analysis from consecutive autopsies of 386 children aged between 2 months and 5 years without vitamin D prophylaxis by Schmorl in Dresden revealed a prevalence of signs of rickets in the 3rd month of life of 61%, from the 4th to the 18th month of 94% to 98%, from the 19th month to the beginning of the third year of 91%, in the third year of 88% and in the fourth year of 71% . Prophylaxis with vitamin D drops was introduced in 1939. From 1947 children in East Germany received oral stoss-prophylaxis with 600,000 units of vitamin D2 at 1, 4, 7 and 11 months of age. Later this regimen was adjusted to 100,000 units of vitamin D3 to prevent hypercalcaemia , , , . Under stoss-prophylaxis no cases of rickets were reported. In East Germany universal oral prophylaxis with 400 units vitamin D3 was introduced from 1989 by a ministerial directive . On a recommended but not universal prophylaxis with 500 IU/day of vitamin D3 Kruse  reported a prevalence of 400 cases of rickets/year in West Germany between 1989 and 1999. In a recent survey across Germany Bergmann et al.  reported 25(OH)D levels from 10,015 0–18 year olds: 65% were below 50 nmol/L, 9% of 0–2 year olds even below 25 nmol/L.
There is debate about the association between 25(OH)D levels and health outcomes. Levels <50 nmol/L are widely regarded as vitamin D deficiency, a target of >50 nmol/L is recommended , , . For adults >75 nmol/L has been proposed as needed to support extraskeletal functions of vitamin D . This has not been confirmed for children , . According to both definitions the majority of our study participants reached sufficient 25(OH)D levels on supplementation with 400 IU vitamin D3/day.
To our knowledge this is the first analysis of a public health program for the prevention of vitamin D deficiency. In keeping with current recommendations 400 IU of vitamin D3 were used for supplementation , , . We consider the approach in former East Germany as unique because this centrally directed program reached the complete outpatient service in the country and determined their clinical practice. Thus the results can be interpreted as being population-based.
There are two studies looking at the impact of universal supplementation in groups at risk of vitamin D deficiency in the UK , . Moy et al.  described that vitamin D supplementation with 400 IU/day led to a 59% fall in the incidence rate of symptomatic vitamin D deficiency and almost universal public awareness of vitamin D deficiency. Similarly, successful routine vitamin D supplementation was reported in refugees in Sydney, Australia .
Alonso et al.  performed a randomised controlled trial in Northern Spain that did not show benefits from universal vitamin D supplementation in healthy children during their first year of life. In contrast to our findings breastfed infants had significantly lower vitamin D levels.
In our study the most significant rise in vitamin D, calcium and ALP levels occurred during the first 3 months of life. There was no difference between infants on breastmilk and vitamin D free formula. Importantly 59% of analyses showed 25(OH)D levels higher than 75 nmol/L on supplementation. 25(OH)D levels decreased at 6 months of age when solids were introduced (Table 1). Considering that human milk contains 25 IU/L of vitamin D or less  compared to an average vitamin D content of 40–100 IU/100 kcal in infant formula and 40–120 IU/100 kcal in follow-on formula , these findings reflect that a combination of fortified formula-use and vitamin D supplementation has a potential to induce elevated 25(OH)D levels. In this context it is of interest that our group could previously demonstrate that supplementation with 250 IU/day is sufficient during the first 8 weeks of life .
Phosphate levels dropped when solids were introduced and milk-consumption was reduced. This has been described previously and is due to higher bioavailability of phosphate from milk-products . ALP fluctuated significantly indicating that during the first 3 months of life (the period of the highest growth velocity during the postnatal period) calcium, vitamin D and bone metabolism are very active and susceptible to alterations. The correlation between 25(OH)D and ALP was weak. This aligns with previous findings that ALP levels cannot be used for screening or monitoring of vitamin D deficiency (Figure 3) .
In the majority of our analyses from 2 to 6 and 8 to 12 months of age, 25(OH)D levels were higher than 75 nmol/L. In contrast to these findings Gallo et al.  reported that 400 IU/day resulted in 25(OH)D levels >75 nmol/L in 55% at 3 months and declined at 6, 9 and 12 months comparing supplementation with 400, 800, 1200 and 1600 IU/day during the first year of life. It was discussed whether the dose of vitamin D should be higher than 400 IU/day under those circumstances . As suggested this might be due to non-adherence but also reflects the decreased relative intake of vitamin D per kilogram bodyweight – this is more significant in infants on 400 IU/day compared to infants on higher doses. In contrast to Gallo et al., Ziegler et al.  showed a similar response profile comparing the use of 200, 400, 600 and 800 IU of vitamin D during the first year of life. They concluded that 400 IU/day should be the preferred dose. As suggested by Abrams  and Paxton et al.  the decision to recommend higher doses of vitamin D should depend on whether future studies provide evidence for the importance of vitamin D levels higher than 50 nmol/L for the prevention of extra skeletal health-risks. Side effects observed in vitamin D sensible infants include tissue calcification and nephrocalcinosis , , , .
In our study a small subset of subjects presented with clinical findings of craniotabes that were not correlated with vitamin D deficiency. In 1969 the prevalence of craniotabes in the region of the present analysis was 6%–8%, which is significantly higher than in our cohort. Historically craniotabes were used to determine the prevalence of rickets. This approach was altered upon realisation that the degree of pressure that a physician put on an infants skull significantly influenced the outcome of the examination. Subsequently biochemical parameters including ALP, calcium and phosphate were preferred. Wolf et al.  examined a cohort of 5043 infants for craniotabes: out of 3540 on continuous prophylaxis with 500 or 1000 units of vitamin D3, 1.6% had craniotabes; out of 1503 on stoss-prophylaxis with one to four doses of 600,000 units of vitamin D3, 2.7% showed signs of craniotabes. 1.6% of children with continuous prophylaxis had craniotabes without biochemical pathology. These findings are very similar to our results of 1.7% of subjects with craniotabes with only minimal biochemical changes.
A limitation of the presented study is that it is observational and findings are cross-sectional. This is outweighed by the large number of participants and the standardised, population-based approach for every visit as outlined in official notes , . We used a competitive protein binding assay with [3H]-25(OH)D developed by Aksnes , . Preparation of the samples included lipid extraction with chloroform/methanol, chromatography similar to high-performance liquid chromatography (HPLC) followed by gel-filtration, separation of beta-lipoproteins of serum proteins and binding studies. For the present study assays were regularly validated using standardised control-samples. Some competitive binding assays were reported to overestimate circulating 25(OH)D levels. One of these was the commonly used Nichols-RIA, this method did not include previous chromatography , . Studies revealed that the Aksnes method is comparable with most of the leading methods at the time . In comparison to the method of Bouillon et al.  it revealed higher values for 13 year olds but good agreement with values from patients treated with pharmacological doses of vitamin D . We are not aware of studies comparing the Aksnes method to liquid chromatography-tandem mass spectrometry (LC-MS/MS). We conclude that the finding that HPLC analyses are in good agreement with LCMS  and the applied quality control measures support the validity of the method used in our study.
Adherence with supplementation was assessed at regular scheduled health screening visits using a questionnaire and documented in the children’s health visit pass. These were regularly checked for non-adherence. In the study documents non-adherence was not mentioned and this is why we assumed that adherence was close to 100%. Looking at our analysis this is also supported by the remarkably low rate of clinical symptoms of rickets and the presence of 25(OH) D levels >50 nmol/L in 84% of tests. A strength of this study is that participants were either breastfed or on non-vitamin D-fortified formula followed by vitamin D free solids. We are not aware of another study using vitamin D-free milk. Thus 25(OH)D levels in this subgroup of our study population represent the direct effect of vitamin D derived from supplementation with 400 IU/day and production in the skin . The difference to breastfed infants reflects the vitamin D content and vitamin D effectiveness in human milk. Infants on a combination of vitamin D fortified formula and vitamin D supplementation are at risk of developing high vitamin D levels , .
The experience from a highly standardised health care system reveals that universal supplementation with 400 IU of vitamin D3 during the first year of life provides sufficient 25(OH)D levels. The range of levels suggests benefits for bone health as well as extra skeletal functions of vitamin D.
We are very grateful to Frieder Deschner, University Children’s Hospital of Jena, Germany and Marlies Rohleder, Children’s Hospital-Lindenhof, Berlin-Lichtenberg, Academic Teaching Hospital of the Humboldt University (Charité) Berlin, Germany for their excellent biochemical analyses.
Author contributions: Dr. Aris Siafarikas and Dr. Volker Hesse conceptualised this paper, drafted the initial manuscript, and approved the final manuscript as submitted. Dr. Alfons Deichl carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Gerhard Jahreis, Dr. Angela Pieplow, Dr. Hartmut Vogel, Dr. Eberhard Kauf, Dr. Anna-Elisabeth Kapuhs, Dr. Elke Badecke, Dr. Gerhard Berger and Dr. Hans Kändler designed the data collection instruments, coordinated and supervised data collection at their site, critically reviewed the manuscript, and approved the final manuscript as submitted. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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