Prescription of vitamin D in neonates and infants under one year of age in Spain: an eight-year observational study

Background

Vitamin D is essential for bone health and immune function, particularly in early life. While its supplementation is widely recommended during infancy, data on prescribing patterns in the pediatric population—especially in a primary health care setting—are limited, particularly in Spain.

Objective

To determine the prevalence and characteristics of vitamin D prescriptions in infants under one year of age in Spain, and to identify potential safety concerns related to off-label use and excipients.

Methods

We conducted a cross-sectional, observational study using prescription data from January 2013 to December 2020. All prescriptions of medications containing vitamin D (cholecalciferol or calcifediol) for infants aged < 1 year in primary health care were analyzed. Variables included were pharmaceutical form, dosage regimen, age indication, prescription requirement, and the presence of mandatory-declaration excipients.

Results

A total of 4,829,158 prescriptions were recorded. Cholecalciferol was the most frequently prescribed active ingredient (96.43%). Considering all vitamin D medications, oral solution was the predominant pharmaceutical form (99.43%), and daily administration was the most common dosing regimen (96.51%). Off-label prescriptions accounted for 4.03% of the total, often involving adult-only formulations or pharmaceutical forms unsuitable for infants, such as tablets/capsules and orodispersible tablets. Several medications included excipients with known pediatric safety concerns, such as ethanol, sorbitol, aspartame, and sucrose.

Conclusion

This large long-term study provides critical insight into vitamin D prescribing practices in primary care for infants in Spain. While most prescriptions aligned with pediatric recommendations, the presence of off-label use and potentially harmful excipients highlights the need for improved regulatory oversight and prescriber awareness.

Highlights

Analysis of 4.8 million vitamin D prescriptions in Spanish neonates and infants aged < 1 year.

96.43% of prescriptions involved cholecalciferol, primarily as an oral solution with daily dosing.

4.03% of prescriptions were off-label, including adult-only or inappropriate formulations for neonates and infants under one year of age.

Several prescriptions contained excipients of mandatory declaration, especially harmful for neonates and infants, such as ethanol and sucrose.

Findings support the need to strengthen pediatric-specific prescribing practices, particularly through improved surveillance of off-label use in primary care.

Introduction

Calcifediol (25-hydroxyvitamin D [25(OH)D]), the main circulating metabolite of vitamin D in the human body, plays a crucial role in calcium homeostasis, bone metabolism, and immune function, acting as a hormone precursor [1]. Calcifediol must be further hydroxylated in the kidneys to its biologically active form, calcitriol (1,25(OH)₂D₃), to exert these hormonal effects. In Spain, clinical recommendations generally follow those of the U.S. Institute of Medicine, which define serum 25(OH)D concentrations of ≥ 50 nmol/L as sufficient for bone health, whereas concentrations < 20 nmol/L are considered indicative of deficiency [2]. Vitamin D deficiency is associated with reduced intestinal calcium absorption, increasing the risk of impaired bone mineralization [3]. In infants, this deficiency may lead to craniotabes and delayed growth, whereas in older children it can result in bone deformities and pain during ambulation [4].

Vitamin D deficiency can result from various causes, including reduced synthesis due to skin phenotype (darker skin requires more sun exposure), excessive use of sunscreen, geographic location (lower synthesis at northern latitudes due to light dispersion), advanced age, smoking, obesity, malabsorption syndromes, renal or hepatic failure, certain medications, pregnancy, and breastfeeding [3, 5].

In recent years, there has been a significant global increase in the number of blood tests performed to measure vitamin D levels, alongside a rise in prescriptions for vitamin D-containing medications [6, 7]. In Spain, according to the Ministry of Health, vitamin D ranks among the top 10 most commonly used medications in the general population [8]. It has been reported that neonates and infants (0–23 months) are particularly susceptible to toxic effects from vitamin D overdose [9].

It is important to point out that, in addition to active ingredients or their combinations, medications also include excipients, which serve as vehicles and ensure the medicine’s preparation and stability, modify its organoleptic properties, and/or determine its physicochemical properties and bioavailability [10]. Some excipients, such as sorbitol, ethanol, aspartame, and sucrose, are subject to mandatory declaration on labelling due to their importance for safe and appropriate medication use. Their safety information is regularly updated based on scientific and technical advances and in accordance with European Union regulations [11].

Studies on vitamin D prescribing in Spanish pediatric primary care are limited and mostly focus on professional surveys or general guidelines [12, 13]. Recent research shows inconsistent adherence to supplementation recommendations and dose variability, especially after the first year [12, 14]. This highlights the need for population-based data to better understand prescribing practices and inform decision-making, particularly in vulnerable groups like children, where formulation suitability and excipient safety are also key considerations.

Given this context, the objectives of this study were, first, to determine the prevalence of prescriptions for vitamin D-containing medications from 2013 to 2020 in neonates and infants aged under 1 year, within the primary health care setting in Spain. Second, to describe and analyze different variables related to these prescriptions, including a review of mandatory-declaration excipients used in vitamin D formulations.

Materials and methods

Study design

A cross-sectional descriptive observational study was conducted on prescriptions for medications containing vitamin D (cholecalciferol and calcifediol). The study period covered 8 years, from January 2013 to December 2020.

Study population and setting

The study analyzed prescription units, meaning that it recorded the total number of medications prescribed rather than the number of individual patients. The study population comprised prescriptions for medications containing vitamin D issued to neonates and infants aged < 1 year within the primary care setting in Spain.

Although the specialty of primary care prescribers was not restricted in the analyzed dataset, primary care pediatricians are recognized as the main point of contact and principal prescribers for children and adolescents within the Spanish public healthcare system, delivering comprehensive and continuous care focused on health promotion and the management of acute and chronic conditions [15].

Study variables

Study variables were categorized based on medication characteristics. The selection of these variables was made after a preliminary analysis of a substantial portion of the data sample [16], with the aim of describing both the medication and the patient. Consequently, prescriptions of vitamin D-containing medications for neonates and infants (< 1 year) were quantified by active ingredient (cholecalciferol or calcifediol), pharmaceutical form (e.g., oral solution, orodispersible tablets, topical forms, tablets/capsules), administration route (oral or topical), active ingredient composition (single or combined active ingredients), and prescription status (prescription-only or over-the-counter). Additionally, prescriptions were also classified by dosing frequency (daily, weekly, monthly, or loading dose) and age indication (pediatric-adult, > 12 years, or adults only (> 18 years)) in the summary of product characteristics (SmPC). Besides, during this preliminary analysis, off-label prescriptions were observed, which was deemed a relevant finding warranting further study. Off-label prescriptions were defined based on the information available in the SmPC retrieved from the CIMA database of the Spanish Agency for Medicines and Medical Devices (AEMPS) [17]. A prescription was considered off-label when at least one of the following criteria was not explicitly authorized for children aged < 1 year: indicated age group, dosage, or pharmaceutical form.

Data source and analysis

Study data collection included the ambulatory prescription records from a private database (complete national scope) sorted by age group and medication characteristics (brand name, active ingredient, strength, pharmaceutical form and package) [16]. The database component used in this analysis included prescription data only and did not incorporate wholesaler, distributor, or pharmacy data (e.g., dispensations). Specifically, the prescription estimates in Spain are derived from a continuously collected and quality-controlled panel which is stratified by medical specialty and geographic region and subsequently weighted to reflect the national prescriber universe, enabling the projected prescription volumes to monthly and quarterly national estimates. The sample is on the order of ~ 900–1,000 physicians (≈ 0.5% of the prescriber universe). In the absence of access to individual medical records, this private database is considered a reliable and widely used source for assessing prescribing behavior, market and trends.

Analysis was performed in Microsoft Excel using absolute numbers and percentages. A descriptive analysis was also conducted on mandatory-declaration excipients, based on product information from the CIMA database of the AEMPS [17] or, if unavailable, from BotPlus, developed by the General Council of Official Colleges of Pharmacists of Spain [18].

Prescription-only medicines and OTC vitamin D products were included when documented by primary care physicians in the prescription record, as OTC products may be entered as a clinical recommendation or reminder despite not requiring a formal medical prescription in Spain.

Off-label use was defined exclusively based on the approved SmPC. Accordingly, the assessment of off-label use did not differ between prescription-only medicines and OTC products, as both were evaluated against the same authorized indications related to target populations, dosages, and routes of administration specified in their respective SmPCs.

Ethical considerations

According to Spanish regulation (Royal Decree 957/2020, of November 3, regulating observational studies with medicinal products for human use), studies related to the units dispensed under medical prescription to evaluate the prescribing tendency are not legally required to obtain permission from the Ethical Review Committee or register the study protocol. Informed consent was also not necessary to request from subjects and/or their legal guardian(s) since an Ethical Review Committee approval of a protocol was not required at this study. All methods were carried out in accordance with relevant guidelines and regulations.

Results

General characteristics of prescriptions analyzed throughout the study period

Between January 2013 and December 2020, a total of 4,829,158 vitamin D prescriptions (cholecalciferol and calcifediol) were issued for neonates and infants aged < 1 year (Table 1). Cholecalciferol was the predominant active ingredient (96.43% of all prescriptions). The most frequently prescribed pharmaceutical form was oral solution, comprising 99.43% of prescriptions. Other forms—topical formulations, orodispersible tablets, and tablets/capsules—collectively accounted for 0.57%. The predominant route of administration was oral (99.73%), compared to topical (0.27%). According to the product information, the most common dosing frequency was once daily (96.51%), followed by weekly (3.39%).

Table 1.

Number and percentage of vitamin D prescriptions in neonates and infants aged < 1 year by study variables

Variable	Category	N	%
Active ingredient	Cholecalciferol	4,656,692	96.43
	Calcifediol	172,467	3.57
Pharmaceutical form	Oral solution	4,801,713	99.43
	Orodispersible tablets	8,796	0.18
	Topical	12,825	0.27
	Tablets/Capsules	5,825	0.12
Route of administration	Oral	4,816,334	99.73
	Topical	12,825	0.27
Dosing frequency	Daily	4,660,458	96.51
	Weekly	163,602	3.39
	Monthly	2,556	0.05
	Loading dose	2,543	0.05
Active ingredient composition	Single active ingredient	4,805,377	99.51
	Combination of active ingredients	23,782	0.49
Prescription requirement	Prescription required	4,812,752	99.66
	Over-the-Counter	16,407	0.34
Indicated age group	Pediatric-Adult	4,634,350	95.97
	> 12 years	19,856	0.41
	adults only (> 18 years)	174,953	3.62
Total		4,829,159	100.00

A total of 99.51% of the prescriptions were for medications with a single active ingredient, whereas 0.49% were combinations of active ingredients. These combinations primarily included cholecalciferol associated with calcium carbonate. However, its use in children < 1 year of age is restricted because no data are available, compared to formulations containing cholecalciferol as the only active ingredient. Regarding prescribing conditions, the vast majority (99.66%) required a medical prescription for dispensing. In contrast, combinations of cholecalciferol with other vitamins and minerals were also identified, but these medications did not require a prescription.

Concerning the age group(s) specified in the SmPC for the prescribed medications in this population (neonates and infants aged < 1 year), 95.97% were labelled as suitable for “pediatric-adult” use. However, 3.62% were labelled “adults only (> 18 years)”, and 0.41% for “> 12 years”, thus constituting off-label prescriptions for the study population.

Year-by-year comparison

Throughout the study period, a slight increase in cholecalciferol prescriptions was observed, peaking in 2020 with 737,420 prescriptions. In contrast, calcifediol prescriptions fluctuated. Notably, there were no prescriptions of calcifediol in 2018. A resurgence occurred in 2019 (N = 19,750 prescriptions), followed by a significant decrease in 2020 (N = 7,729). Figure 1 depicts the yearly proportion of prescribed medications containing cholecalciferol or calcifediol, confirming the dominance of cholecalciferol formulations and the marginal contribution of calcifediol, which reached 0% in 2018.

Fig. 1.

Percentage of prescribed vitamin D in neonates and infants aged < 1 year by active ingredient (cholecalciferol and calcifediol)

Oral solution remained the most commonly prescribed form of vitamin D in neonates and infants < 1 year across the years, with increasing use from 2017 and a peak in 2020 (N = 743,663). Orodispersible tablets and tablets/capsules were also prescribed, despite being unsuitable for the studied age group; peak years were 2016 and 2019, respectively. Topical formulations were used in the early study years but were no longer prescribed after 2014 (Fig. 2).

Fig. 2.

Percentage of prescriptions of vitamin D in neonates and infants aged < 1 year by pharmaceutical form

Throughout the study period, daily dosing was the predominant regimen for neonates and infants < 1 year, representing 96.51% of prescriptions (N = 4,660,458) and reaching the highest number in 2020 with 745,149 prescriptions. Most medications contained a single active ingredient (99.51%, N = 4,805,377) and required a formal prescription (99.66%, N = 4,812,751). Weekly administration displayed intermittent peaks, with a maximum of 80,751 prescriptions in 2018, followed by a gradual decline. Monthly and loading-dose regimens were rare, appearing only in isolated years (monthly in 2013 and 2019, loading in 2014) (Fig. 3).

Fig. 3.

Percentage of vitamin D prescriptions in neonates and infants aged < 1 year by dosage regimen

As for proportion of off-label prescriptions by dosing regimen, prescriptions in this population (neonates and infants aged < 1 year) within the age indication were only identified for the daily dosing regimen, while weekly, monthly, and loading dose regimens were prescribed off-label in 100% of cases (Table 2).

Table 2.

Percentage of off-label prescriptions of vitamin D in neonates and infants aged < 1 year according to dosing regimen

	Total prescriptions	Off-label prescriptions	% off-label prescriptions
Daily	4,660,458	26,109	0.56%
Weekly	163,602	163,602	100.00%
Monthly	2,556	2,556	100.00%
Loading dose	2,543	2,543	100.00%

Regarding the age groups indicated in SmPC (Fig. 4), the majority of vitamin D prescriptions for neonates and infants aged < 1 year were intended for the “children–adults” age group. An upward trend was observed over the study period (January 2013 – December 2020), with the peak year in 2020 (N = 743,663 prescriptions). By contrast, prescriptions of vitamin D products labelled for individuals over 12 years of age were primarily observed during the first two years of the study, although a notable number of prescriptions was also recorded in 2019 (4,488). Meanwhile, prescriptions for medications indicated for adults over 18 years occurred in all years except 2014, with the highest number recorded in 2018 (N = 83,589 prescriptions). In total, 194,809 prescriptions (4.03%) of vitamin D issued to neonates and infants aged < 1 year were off-label for this age group.

Fig. 4.

Percentage of vitamin D prescriptions in neonates and infants aged < 1 year by the age group indicated in the summary of product characteristics (SmPC)

Safety regarding excipients in vitamin D medications

In the analysis of medications prescribed between 2013 and 2020 to neonates and infants aged < 1 year, some vitamin D medications were found to contain excipients subject to mandatory declaration. This was the case for one product containing calcifediol (N = 1,337 prescriptions), another product containing a calcium/cholecalciferol combination (N = 2,838 prescriptions), and the third product containing a combination of cholecalciferol with vitamins and minerals (N = 15,176 prescriptions), as shown in Table 3.

Table 3.

Specific medications of vitamin D prescribed to neonates and infants < 1 year, including active ingredient concentrations and excipients subject to mandatory declaration

Active ingredient concentrations*	Excipients
Calcifediol 266 µg/mL	Anhydrous ethanol, glycerol, sorbitol 70% solution, orange-yellow colorants (E110, CI = 15985)
Calcium carbonate 600 mg / Cholecalciferol 400 UI	Sorbitol, aspartame (E-951), sodium croscarmellose, sodium saccharin, lactose monohydrate, partially hydrogenated soybean oil, sucrose
Sodium fluoride 0.50 mg / Vitamin A 750 UI / Vitamin B1 1.00 mg / Vitamin B2 1.00 mg / Vitamin PP 10.00 mg / Vitamin C 50.00 mg / Cholecalciferol 200 UI / Vitamin B6 1.00 mg / Vitamin E 10.00 mg	Disodium edetate, polysorbate 80, sodium saccharin (3 mg), propylene glycol, glycerol (E-422), banana essence, vanilla essence, thioglycerol, purified water and 70% sorbitol

* The concentrations correspond to the commercial presentations analyzed in this study

Discussion

This large, long-term observational study aimed to determine the prevalence and characterize the patterns of vitamin D prescribing for neonates and infants < 1 year of age in primary care in Spain from 2013 to 2020. Given the critical role of vitamin D in early development and the specific vulnerabilities of this population to medication errors and excipient-related adverse effects, understanding real-world prescribing practices is essential for optimizing patient safety.

According to the National Institute of Statistics, between 341,315 and 427,595 births were registered annually in Spain during the study period [19]. While individual prescribing patterns cannot be inferred from these data, the findings suggest that off-label use of vitamin D in infants is a frequent practice in routine clinical care, rather than an isolated or exceptional occurrence, thereby supporting the clinical plausibility of the results.

Our analysis of over 4.8 million prescriptions provides a detailed view of prescribing patterns. The primary results indicate that vitamin D prescribing was overwhelmingly dominated by cholecalciferol (96.43%), primarily in the form of an oral solution (99.43%) administered daily (96.51%). This aligns with international recommendations for vitamin D supplementation in infancy. However, a secondary and critical finding was that 4.03% (N = 194,809) of all prescriptions were off-label, meaning the medications were not authorized for this age group according to their SmPC. These off-label prescriptions included formulations indicated only for adults (> 18 years) or for children over 12 years, as well as pharmaceutical forms unsuitable for infants, such as tablets/capsules and orodispersible tablets. The existence of multiple commercial presentations, in which doses are expressed in different ways (e.g., IU per mL, per 2.5 mL, or per 5 mL) could contribute to confusion and use medicines intended for people over 12 years. Topical formulations, observed only in the early study years (2013–2014), were progressively discontinued due to their limited systemic absorption and lack of evidence in infants, consistent with their later withdrawal from pediatric practice.

In 2004, the European Medicines Agency (EMA) published a report on the unauthorized use of medicines in children [20], which highlighted that off-label use is associated with a higher incidence of adverse drug reactions (ADRs). These ADRs are different and often more severe and less predictable compared to those observed in adults. From a clinical perspective, the lack of age-appropriate medications and dosage recommendations in primary care often forces clinicians to extrapolate from adult data, increasing the risk of dosage inaccuracies, as pediatric dosing is frequently more complex than simply reducing the adult dose based on a child’s age or weight [21]. This challenge becomes particularly critical in hospital settings—especially in neonatal and pediatric intensive care units—where infants < 1 year of age are exposed to a high burden of medications and physiological immaturity markedly increases vulnerability to toxicity [22].

Regulation (EC) No 1901/2006 promotes the development and availability of medicines for pediatric use in the EU. This includes the creation of a Pediatric Committee (PDCO), which requires pediatric data in clinical trials and offers incentives such as patent extensions. The regulation also defines procedures to ensure the safety and efficacy of pediatric medicines [11]. As confirmed by the 2010 EMA report on the use of pediatric medicines in Europe, off-label prescribing remains a routine component of pediatric clinical practice, reflecting persistent unmet therapeutic needs and a lack of evidence-based pediatric pharmacotherapy [23]. According to the European Commission (2017) report on 10 years of the EU Pediatric Regulation [24], early assessments suggested greater availability of pediatric medicines in certain therapeutic areas, such as rheumatology and infectious diseases; however, from a clinical perspective, progress has been limited in many conditions, particularly rare diseases and those requiring child-specific formulations. These findings underscore the continued need for clinical research and development of pediatric medications to support safer and more effective prescribing decisions for children. Despite these regulatory efforts, off-label use of medications in pediatric care has remained substantial across Europe, as highlighted by more recent studies. A study published in 2017, analyzing data from 2000 to 2015 [25], reported that off label drug use in pediatric care across European countries ranged from 13% to 69% in hospital settings and from 2% to 100% in primary care settings.

In the Spanish context, in 2019, AEMPS issued a safety warning regarding vitamin D use [26], reporting serious cases of hypercalcemia due to overdose in both adult and pediatric patients. In all pediatric cases, doses used were significantly higher than recommended, and in some cases, off-label medications indicated only for adult use were administered to children. In the present study, an increase in off-label prescriptions was observed until 2018, with the highest prevalence that year. Notably, immediately after the publication of the safety alert, prescriptions decreased sharply, with an approximate 75% reduction in 2019 compared with 2018. This downward trend continued in the following year, resulting in an overall reduction of nearly 98% in 2020 relative to pre-alert levels in 2018.

Intermittent peaks in vitamin D prescriptions, particularly in 2018 and 2020, appear to reflect contextual factors. The 2018 increase coincided with a temporary clinical preference for intermittent regimens, which declined following the 2019 AEMPS alert on pediatric hypercalcemia. By contrast, in 2020, vitamin D prescriptions for neonates (< 1 year) peaked at 745,149, coinciding with the COVID-19 pandemic. This rise may reflect concerns about immune function and COVID-19 severity, as early studies suggested potential benefits of adequate vitamin D levels [27–29]. Lockdowns and reduced sun exposure likely increased concern about deficiency, particularly among vulnerable populations such as infants [27]. A South Korean study also reported a reduction in neonatal deficiency during this period, attributed to increased maternal supplementation [30]. Although the present study does not establish a direct causal link, converging evidence from prescription trends and national consumption data strongly suggests that vitamin D use in Spain increased during the lockdown months of March–June 2020 [31].

In this study, cholecalciferol was the most prescribed vitamin D for neonates and infants aged < 1 year in Spain, with a moderate upward trend and a peak in 2020 (737,420 prescriptions). The predominance of cholecalciferol over calcifediol – authorized for the treatment of vitamin D deficiency in children < 12 years of age and adolescents [32] – is pharmacologically consistent with current pediatric recommendations. Cholecalciferol undergoes hepatic conversion to calcifediol, allowing physiological regulation of its activation and reducing the risk of overdose. In contrast, calcifediol bypasses this control step and has a narrower therapeutic window, which makes it less suitable for neonates despite its higher potency [33].

Furthermore, our excipient analysis identified that certain prescribed products contained mandatory-declaration excipients. These considerations are particularly relevant for newborns and infants under one year of age, whose primary source of intake is breast milk or infant formula and who have limited exposure to other dietary or environmental sources of excipients. In this context, the presence of specific excipients — such as anhydrous ethanol, sweeteners, or coloring agents — may warrant careful consideration since they would be not recommended due to age-specific physiological vulnerability in the pediatric population, triggering potential toxicity. In this cases, prescribers’ limited awareness of the excipients contained in these medications including which ones require mandatory declaration could be the reason of an unintentional error.

Among the mandatory declaration excipients used in vitamin D medicines is sucrose, which is associated with dental caries and is contraindicated in diabetic patients depending on the dose [34]. In our study, sucrose was identified in 2,838 prescriptions. In addition, sorbitol and aspartame were present in 4,175 and 2,838 prescriptions, respectively. Both excipients belong to the same family of sweeteners. Sorbitol has the potential to accumulate in the body and has been linked to diabetic complications, including retinopathy and cataracts. For this reason, its concentration in pediatric formulations is limited to 0.3 mg/kg body weight; nevertheless, given the small volumes typically administered, actual exposure in clinical practice is likely to be considerably lower [35]. Similarly, although the maximum acceptable daily intake of aspartame is set at 40 mg/kg body weight and its metabolites have been examined for potential neurotoxic effects and associations with type 2 diabetes and cardiovascular disease, the amounts present in pediatric formulations remain below these established safety thresholds [36]. In the case of the excipient anhydrous ethanol (N = 1,337 prescriptions), Circular No. 1/2018 from the Spanish Ministry of Health stated that “ethanol content must be considered in pregnant or breastfeeding women, children, and high-risk populations such as patients with liver disease or epilepsy” [34]. In line with this regulatory guidance, international pediatric safety recommendations highlight that ethanol exposure in children may be associated with central nervous system depression and hypoglycemia and advise limiting its concentration to a maximum of 5% v/v in children under 6 years of age, with use restricted to situations under appropriate clinical supervision [37].

Ethanol is regulated by the EMA and its use in pediatric populations is generally not recommended. Given that vitamin D medicines are typically administered on a daily, long-term basis rather than intermittently, it is important to clearly acknowledge this aspect when interpreting potential cumulative exposure. Given its known toxicity and the potential for adverse effects even at low doses, the presence of ethanol in products intended for infants represents a significant safety concern, underscoring the need for heightened prescriber awareness and stricter regulatory oversight, particularly when ethanol-free alternatives are available [38].

Despite the EMA’s efforts to harmonize the definition of mandatory excipient declaration and establish safety intake thresholds, regulatory inconsistencies persist. For instance, artificial sweeteners (e.g., aspartame, saccharin) and certain coloring agents are prohibited in foods for children under three years of age but remain present in medications authorized for this population. In infants who have not yet initiated food diversification, early exposure to some of those excipients may increase the risk of adverse events, allergies, or intolerances that may otherwise go unnoticed [39].

Study limitations

This study has limitations that may affect the estimated prevalence of vitamin D prescriptions in children aged < 1 year. The dataset analyzed includes prescriptions issued in primary care only and does not allow confirmation of medication dispensation or actual use. Prescriptions from specialist care and hospital settings are not captured, nor are non-prescription medicines used for self-care (e.g., OTC supplements not recorded within a prescription). Nonetheless, the large eight-year sample offers robust insight into pediatric prescribing patterns in Spain.

Due to the nature of the prescription database used as the data source, all reported numbers represent national estimates extrapolated from a representative sample of prescribing physicians and do not correspond to absolute counts for the entire national population. Besides, the data were not linked to clinical records (e.g., medical history, diagnosis, or specific treatment), which prevents determining whether multiple prescriptions corresponded to the same patient. Although this approach allows for a comprehensive assessment of prescribing trends at a population level, it constitutes a methodological limitation that should be considered when interpreting prevalence estimates.

Finally, medication characteristics (excipient content, active ingredient, dose, and pharmaceutical form) were obtained from the CIMA database, reflecting product information available at the time of data collection and not accounting for potential formulation changes during the study period.

Conclusions

This study analyzed a large long-term prescription history of vitamin D in primary health care in Spain for children aged < 1 year, with a total of 4,829,159 prescriptions recorded. Most prescriptions were for cholecalciferol oral solution with a daily dosing regimen. Specifically, the predominant active ingredient was cholecalciferol, representing 96.43% (4,656,692) of the total. Regarding the pharmaceutical form, oral solution was the predominant form in 99.43% (4,801,713) of cases, while a daily dosing regimen was the most common, accounting for 96.51% (4,660,458) of prescriptions.

A total of 194,809 (4.03%) off-label prescriptions were identified, meaning the medications were authorized for use only in patients > 12 years of age according to their SmPC. With regards to mandatory-declaration excipients, substances such as sucrose, aspartame, sorbitol, and anhydrous ethanol—which should be used with caution or avoided in pediatrics—were found in 4,175 prescriptions (0.08% of the total analyzed).

Implications for practice

This study provides a history of long-term prescribing patterns of vitamin D in neonates and infants < 1 year of age within primary health care in Spain. The findings reveal that although the majority of prescriptions adhered to current recommendations (cholecalciferol, oral solution, daily regimen), there is a non-negligible proportion of off-label use and prescriptions involving potentially unsafe excipients for the pediatric population. These results highlight the need to strengthen pharmacological guidance and regulation regarding vitamin D use in infants, especially considering excipient safety and appropriate formulation. Such information is essential for pediatricians, pharmacists, and regulatory bodies to improve medication safety and optimize early-life nutritional interventions.

Authors’ contributions

1. Camila Jorge-Novoa: Main participation in the conception of the study, data collection and analysis, and initial writing of the manuscript. 2. Irene Lizano-Díez: Support in the methodological design, data processing and preparation of tables and results. Contribution to the drafting of the article. 3. Montserrat Viñas-Bastart: Collaboration in the bibliographic search, interpretation of the results and writing of sections of the manuscript. 4. Antonio J. Braza (corresponding author): General coordination of the study, integration of results and critical review of the preliminary versions of the article. 5. Mónica Muñoz-Cortés: Contribution to the clinical and practical interpretation of the results, as well as to the critical review of the manuscript. 6. Carlos Figueiredo-Escribá: Support in the design of the project and in the validation of the analyses carried out. Substantive review of the article and completion of the statistical part of it. 7. Eduardo L. Mariño: Contribution of conceptual and methodological ideas, supervision of the project and critical review of the final version of the manuscript. 8. Pilar Modamio (corresponding author): Supervision and global monitoring of the project, methodological and conceptual orientation, and final critical review before approval of the manuscript for publication.

Funding

The study was carried out without the use of any source of financing.

Data availability

The data will be made available upon reasonable request. Interested parties can contact the corresponding authors (PM: [pmodamio@ub.edu](mailto:pmodamio@ub.edu); AJB: [braza@ub.edu](mailto:braza@ub.edu) ) for inquiry.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.