MOnitored supplementation of VItamin D in preterm infants (MOSVID trial): study protocol for a randomised controlled trial
Kołodziejczyk et al. Trials
MOnitored supplementation of VItamin D in preterm infants (MOSVID trial): study protocol for a randomised controlled trial
Alicja Kołodziejczyk 0
Maria K. Borszewska-Kornacka 0
Joanna Seliga-Siwecka 0
0 Neonatal and Intensive Care Department, Medical University of Warsaw , Karowa 2 Street, 00-315 Warsaw , Poland
Background: The pivotal role of vitamin D (vit D) in skeletal health is well known. Neonatal vit D storage at birth is dependent on maternal levels, and newborns receive 50-70% of their mother's 25-hydroxyvitamin D [25(OH)D]. Deficiency of vit D can lead to prematurity bone disease, with an incidence of up to 55% in infants weighing < 1000 g. The aim of this study is to assess the effectiveness of monitored supplementation of vit D in a population of preterm infants. Methods/design: Preterm infants born at 24-32 weeks of gestation will be recruited within the first 7 days of life. Depending on the type of feeding, and after reaching partial enteral feeding or at 7 days of life, vit D supplementation will consist of 500 IU and an additional 150-300 IU/kg included in human milk fortifiers (if fed exclusively with breast milk) or 190 IU/kg in milk formulas. Subjects will be randomised to either monitored (with an option of dose modification based on 25(OH)D levels as per protocol) or standard therapy up to 52 weeks of post-conceptional age (PCA). The primary outcome measure will be the number of neonates with deficiency or excess levels of 25(OH)D at 40 ±2 weeks of PCA. Additional 25(OH)D levels will be measured at birth, at 4 and 8 weeks of age, and/or at 35 and 52 ±2 weeks of PCA. Secondary objectives will include the incidence of osteopenia, nephrocalcinosis and nephrolithiasis. Serum parameters of calcium phosphorus metabolism will also be measured. Discussion: Despite multiple years of research and numerous publications, there is still a lack of consensus in regard to how much vit D infants should receive and how long they should receive it. Because 80% of calcium and phosphorus placental transfer occurs between 24 and 40 weeks of gestation, preterm infants are especially prone to adverse effects of vit D insufficiency. However, both inadequate and excessive amounts of vit D may be unsafe and lead to serious health issues. The results of our study may shed new light on these concerns and contribute to optimising vit D supplementation. Trial registration: ClinicalTrials.gov, NCT03087149. Registered on 15 March 2017.
Vitamin D; Osteopenia; Prematurity
The pivotal role of vitamin D (vit D) in skeletal health is
well known. The discovery of receptors for vit D in most
tissues and cells has provided new insights on its role in
non-skeletal health. These actions include, among
others, regulation of cellular proliferation, apoptosis and
Studies have shown that in both term and preterm
infants, neonatal vit D storage at birth is dependent on
maternal 25-hydroxyvitamin D [25(OH)D] because the foetus
secures all its vit D from the mother. At birth, regardless of
gestational age (GA), neonatal 25(OH)D levels are 50–70%
derived from mother’s [
In the population of infants born prematurely, vitamin
D deficiency (VDD) can lead to prematurity bone
disease, which is described by different names as rickets of
prematurity, osteopenia of prematurity or metabolic
bone disease (MBD) of prematurity. The incidence of
this morbidity can reach up to 55% in infants weighing
< 1000 g [
]. In this group of neonates, VDD may also
lead to an increased risk of respiratory tract infection
and chronic respiratory morbidity such as
bronchopulmonary dysplasia (BPD), as well as seizures and growth
In order to prevent VDD, recommendations for vit D
supplementation have been published. The American
Academy of Pediatrics guidelines recommend
supplementation of 200–400 IU/day in enterally fed preterm
], whereas in Europe, according to European
Society for Paediatric Gastroenterology, Hepatology and
Nutrition (ESPGHAN) guidelines, supplementation of
vit D for preterm infants should reach 800–1000 IU/day
Recently, separate guidelines have been published for
Central Europe. Preterm infants fed enterally should
receive vit D supplementation of 400–800 IU/day within
the first days of life and continue up to 40 weeks of GA.
This should be followed by 400 IU/day [
Researchers in two prospective observational studies
have assessed recent recommendations for vit D
supplementation. Monangi et al. [
] published a paper
evaluating vit D status in 120 preterm infants (≤32 weeks of
gestation) at birth and at 36 weeks post-menstrual age or
discharge. Daily vit D intake was based on parenteral
nutrition, human milk, human milk fortifier or milk formula,
as well as vit D supplementation of 200 IU/day.
Proportions of 64% of infants at birth and 35% infants at 36 weeks
of post-conceptional age (PCA) or at discharge had serum
25(OH)D concentrations < 20 ng/ml. The authors
concluded that low vit D status at birth and suboptimal vit D
intake were responsible for insufficient 25(OH)D levels in
the population of studied infants [
A study conducted by Pinto et al. [
] in Australia in
2015 evaluated vit D status in 28 infants (30–36 weeks of
gestation) at birth and at 36 weeks PCA [
with Monangi et al.’s trial, total daily vit D was increased
due to higher vit D supplementation of 400 IU/day. The
proportion of infants with VDD decreased from 32.1% to
7.1%, (p = 0.016). However, this study was small in
numbers and excluded extremely low birth weight (ELBW)
infants, in whom the risk of VDD is the highest [
Two randomised studies have become available since
the publication of new recommendations for vit D
supplementation among preterm infants. In a randomised,
double-blind trial done in North India, investigators
enrolled 96 infants (28–32 weeks of GA) in two groups: vit
D 400 IU/day vs vit D 800 IU/day. The primary outcome
was VDD at 40 weeks of post-menstrual age. Secondary
outcomes included VDD, bone mineral content and
density at 3 months of corrected age (CA). The prevalence of
VDD (defined as < 20 ng/ml) in the 800 IU/day group was
significantly lower than in the 400 IU/day group at
40 weeks of PCA (38.1% vs 66.7%, relative risk [RR] 0.57,
95% CI 0.37–0.88) and at 3 months of CA (12.5% vs 35%,
RR 0.36, 95% CI 0.14–0.90). One infant in the 800 IU/day
group had vit D hypervitaminosis (> 100 ng/ml). Bone
mineral content and bone mineral density did not differ
between groups. Again, this trial did not included infants
born ELBW, who are at most risk of VDD, as well as
supplementation-induced hypervitaminosis, immediately
after birth. Considering these factors, we hypothesise that
this population would probably benefit the most from
sufficient vit D supplementation [
Researchers in a U.K. trial randomised 100 infants
(from 23 to 28 weeks of GA) to three groups: placebo
(routine vit D supplementation in parenteral and
enteral nutrition), 200 IU (additional 200 IU/day) or 800 IU
(additional 800 IU/day). Infants in the 800 IU/day group
presented with higher 25(OH)D concentration (p < 0.05).
The incidence of death, BPD, necrotizing enterocolitis
(NEC) or intracranial haemorrhage did not differ between
the study groups. The authors concluded that ESPGHAN
recommendations led to overdosing vit D (> 50 ng/ml) in
many infants, whereas routine intake of an additional
200 IU/day allowed more infants to reach recommended
As shown by the above studies, inappropriate vit D
supplementation may lead to VDD or vitamin
overdosing and mild hypercalcemia [
]. The dosage, safety and
effectiveness of vit D supplementation in preterm infants
remain controversial topics. Clear criteria for adequate
25(OH)D levels in preterm infants have not been
established. In view of inconsistent and insufficient data,
several authors have suggested that vit D supplementation
should be monitored in the preterm population [
The main objective of the present trial is to assess the
effectiveness of monitored supplementation of vit D in a
population of preterm infants born at 24–32 weeks of
gestation with the aim of optimising 25(OH)D levels
measured at 4 and 8 weeks of age and/or 35, 40 and
52 weeks of PCA. We hypothesise that monitored
therapy is more effective and safer than standard therapy in
infants given vit D supplementation. Secondary
objectives are to assess the effect of vit D on the prevalence
of osteopenia, nephrocalcinosis and nephrolithiasis.
We are conducting a pragmatic, unblinded, parallel-group,
randomised controlled superiority trial.
Setting and participants
Infants born at 24–32 weeks of gestation will be
considered for inclusion. Parents will be approached
shortly after birth and admission to the neonatal
intensive care unit at Princess Anne Hospital in Warsaw,
Poland (a tertiary level perinatal centre, Neonatal and
Intesive Care Department, Medical University of
Warsaw). Caregivers of eligible infants will be invited to
take part in the study. After providing oral and written
information about the study, informed consent will be
obtained by one of the research team members.
Preterm infants will be randomly assigned to a monitored
group or a standard group. Later, a blood sample will
be obtained within the first week of life to assess
25(OH)D levels at birth. At day 7 of life or when
reaching 100 ml/day of enteral feeding, all infants will
receive 500 IU of vit D with an additional 160 IU/kg of
vit D included in parenteral nutrition. Infants will
receive supplementation up to 52 weeks of PCA. All
procedures will take place at the Neonatal and Intensive
Care Department, Medical University of Warsaw.
We will include all preterm infants born between 24 and
32 weeks of gestation (outborns must be admitted within
48 h after delivery). At the time of recruitment,
caregivers must be willing to return for follow-up visits and
provide written informed consent.
We will exclude the following infants: those born
at > 32 weeks of gestation, and those with major
congenital abnormalities, cholestasis or severe illness at birth
deemed incompatible with survival. Exclusion criteria will
also include lack of written informed consent as well as
communication difficulties with caregivers.
Participants will be randomised within the first 7 days of
life after re-evaluating inclusion and exclusion criteria.
Initially, all infants will receive 500 IU of vit D
(cholecalciferol/Devikap; Polpharma, Starogard Gdański, Poland).
After full enteral feeding is reached, depending on the type
of feeding, vit D supplementation will consist of 500 IU
and 150–300 IU/kg included in human milk fortifiers (if
fed exclusively with breast milk) or 190 IU/kg in milk
formulas. At 4 weeks of age, blood samples for 25(OH)D
levels will be obtained, followed by subsequent
measurements at 8 weeks of age and/or 35, 40 and 52 weeks of
PCA. In the monitored group, vit D doses will be
appropriately modified on the basis of 25(OH)D levels (Fig. 1).
We hypothesise that most cases of VDD in infants will be
secondary to an initial low maternal vit D level. Thus, in
these cases, we are planning to increase vit D
supplementation by 500 IU because this will allow reaching a higher
recommended level of 1000 IU/day [
Infants randomised to standard therapy will only have
blood samples obtained in the same fashion as the
monitored group, but no dosing changes will be applied.
Allocation concealment and blinding
Opaque, sealed envelopes labelled with consecutive
study numbers will be allocated to included patients.
The block size will be blinded until completion of the
study. These envelopes will contain index cards with the
allocated treatment. The statistical team, which will not
take part in enrolling infants or in follow-up, will
generate the allocation sequence. The randomisation list will
remain with the statistical team for the duration of the
study. Neonates fulfilling inclusion criteria will be
enrolled after admission. A member of the recruitment
team will randomise enrolled patients. He/she will open
an envelope labelled with the allocated participant
number and inform the primary care physician about the
study group. Due to the nature of the intervention,
neither participants nor physicians applying the
intervention can be blinded to allocation. A staff member not
involved in recruitment and treatment of patients will
collect appropriate data to allow researchers to analyse
results without having access to information about the
allocation. All patient and study information will be
stored on a secure, password-protected, Web-based
Prior study initiation, an introductory meeting will be
scheduled. The session will include the following:
Brief presentation of the study
Instructions about randomisation for personnel who
will take part in patient allocation
Instructions about monitored supplementation and
A subsequent meeting will take place 2 months after
the start of the study. Staff will be asked about any
problems they might be experiencing with implementing the
study, such as patient recruitment, randomisation and
treatment allocation. Prior to discharge, caregivers of
included infants will receive oral and written instructions
about vit D application. Depending on the neonate’s
PCA, follow-up visits will be scheduled as per protocol.
The number of neonates with deficient or excess
25(OH)D levels at 40 ± 2 weeks of PCA will be the
primary endpoint. Additional 25(OH)D levels will be
measured at birth; at 4 and 8 weeks of age; and/or at 35 and
52 ± 2 weeks of PCA. Venous blood samples will be
collected into glass specimens by neonatal nurses to assess
25(OH)D levels in pre-specified time frames (Fig. 1). An
automated quantitative test available at the study site,
VIDAS® (bioMérieux, Marcy l’Etoile, France), will be
used to measure 25(OH)D. The analyser’s calibration
will be checked with appropriate controls as per product
guidelines. The definitions for vit D status differ slightly
between local and global health authorities [
13, 19, 20
On the basis of our geographical location and the fact
that none of the published documents offer a separate
25(OH)D reference range for preterm infants, we chose
to follow the most recent recommendations for Central
Deficiency: 0–20 ng/ml (0–50 nmol/L)
Suboptimal concentration: > 20–30 ng/ml
(> 50–75 nmol/L)
Optimal concentration: > 30–50 ng/ml
(> 75–125 nmol/L)
Increased level: > 50–100 ng/ml (125–250 nmol/L)
Potentially toxic level: 100–200 ng/ml
Toxic level: > 200 ng/ml (> 500 nmol/L)
The exact incidence of osteopenia remains unknown, in
part owing to the lack of consensus on its definition. We
have chosen to define MBD as decreased bone mineral
content relative to the expected level of mineralisation for
a foetus or infant of comparable size or GA, seen in
conjunction with biochemical and/or ultrasound changes.
Neonatal nurses will collect venous samples for serum
alkaline phosphatase (ALP) and phosphate (P) levels at 35,
40 and 52 ± 2 weeks of PCA. The AU480 chemistry
analyser (Beckman Coulter, Brea, CA, USA) will be used to
perform the measurements. The analyser’s calibration will
be checked with appropriate controls as per product
Additionally, we plan to assess average bone mass
(ABM) using quantitative ultrasound (Sunlight PREMIER
7000; BeamMed, Petah Tikva, Israel). This safe,
noninvasive, radiation-free and easy-to-use method has been
suggested as a screening tool for detecting osteopenia in
premature infants [
]. With placement of a small
ultrasound probe (CRB probe RoHS 900–1000 kHz) along
the mid-tibia, this device measures speed of sound (SOS)
in meters per second in the axial transmission mode. High
intra-individual variation does not allow definition of
normal values. However, in a recently published study,
preterm infants (24–28 weeks of GA) examined at 40 weeks
of PCA showed significantly lower SOS than term infants
]. In order to evaluate infants receiving monitored vit
D therapy, SOS will be higher than with standard therapy,
indicating increased ABM. Two previously trained
neonatologists not participating the study and blinded to group
allocation will assess ABM in each enrolled patient at 35
and at 40 ± 2 weeks of PCA. The measurements will be
made on the tibia. The mid-tibial shaft length will be
determined by measuring the distance from the knee to
the heel. The probe will be placed over the medial aspect
of the mid-shaft tibia to obtain an SOS measurement.
Three measurements will be performed. The mean value
of these measurements will be used for the data
analysis. We decided to define MBD as serum levels of
ALP > 500 IU and P < 1.8 mmol/L [
Nephrocalcinosis and nephrolithiasis
Neonatal nurses will collect venous samples for serum and
urine calcium, P and creatinine levels at 35, 40 and 52 ±
2 weeks of. The AU480 chemistry analyser will be used to
perform the measurements. The analyser’s calibration will
be checked with appropriate controls as per product
guidelines. Hypercalcaemia will be defined as serum
levels ≥ 2.65 mmol/L. Hypercalciuria will be measured by
calculating urine calcium/creatinine ratios [
urine calcium and creatinine are risk factors for
nephrolithiasis in infants. P deficiency suppresses parathyroid
hormone activity and initiates 1,25-(OH)2D synthesis,
leading to hypercalcaemia, hypercalciuria and increased P
kidney reabsorption. Tubular reabsorption of phosphate
(TRP) is a widely accepted indicator of inadequate P
intake. TRP is calculated from phosphorus/creatinine ratio
in the urine and serum. TRP > 95% with P < 1.8 mmol/L is
highly suggestive of osteopenia [
In preterm infants, ultrasonography has proven good
intra-observer reproducibility (kappa = 0.84) and is a
reliable tool for detecting nephrocalcinosis [
]. A trained
ultrasonographer will assess subjects for nephrolithiasis at
35 and 52 ± 2 weeks of PCA using the HD11 XE
ultrasound system (Philips Healthcare, Andover, MA, USA).
Increased medullar echogenicity (small white flecks in the
tip of the pyramids) will be considered as nephrocalcinosis
]. Photographic documentation will be obtained.
We will define an adverse event as any untoward medical
occurrence in a subject without regard to the possibility of
a causal relationship. Adverse events will be collected after
the subject has provided consent and is enrolled in the
study. All adverse events occurring after entry into the
study and until hospital discharge will be recorded. An
adverse event that meets the criteria for a serious adverse
event (SAE) between study enrolment and hospital
discharge will be reported to the local ethics committee. An
SAE for this study is any untoward medical occurrence
that is believed by the investigators to be causally related
to the study intervention and results in any of the
following: life-threatening condition (that is, immediate risk of
death), severe or permanent disability, and prolonged
hospitalisation. SAEs occurring after a subject is discontinued
from the study will not be reported, unless the
investigators feel that the event may have been caused by the study
drug or a protocol procedure.
Retention of participants in the study
Because most of the included patients face long-term
hospital care, we will focus mainly on efficient staff
education and sufficient management of the trial by the
study team. All medical records (MRs) of included
patients will be appropriately labelled with brightly
coloured stickers indicating the study group, monitored
or standard therapy accordingly. Once per week, one of
the team members will audit MRs to schedule
appropriate assessments and laboratory samples. Additionally,
every week, he/she will provide the attending physician
with a list of planned interventions and assessments. We
will organise bi-monthly departmental meetings to
follow any concerns related to the trial.
At discharge, parents of included infants will receive
oral and written instructions on vit D administration
and scheduled follow-up appointments. Parents will
receive a reminder text message 1 day before the
scheduled visit. Caregivers of included infants will be free to
contact the principal investigator at any time.
A data monitoring committee has not been established,
because the intervention in the trial (vit D 200–1000 IU)
does not differ from the standard of care accepted by
several paediatric societies [
]. The profile of potential
side effects is also known.
Sample size calculations
The sample size was calculated on the basis of the main
outcome, defined as the number of neonates with
deficient or excess levels of 25(OH)D at 40 ± 2 weeks of
]. To meet acceptable recruitment rates and to
obtain statistically significant results, we chose to detect
a decrease of 25% in the number of patients with VDD
with a power of 80% and an α value of 0.05; hence, 57
infants are needed in each study group. In order to
account for 20% loss to follow-up, we aim to recruit a
total of 138 infants for the study.
Abbreviations: DOL Day of life, Ca/P Calcium/phosphate ratio, 25(OH)D 25-Hydroxyvitamin D, PCA Post-conceptional age, US Ultrasound, Vit D Vitamin D,
WKA Weeks of age
aOnly infants born at < 26 weeks of gestational age
Statistical analysis will be performed using Statistica
13.1 software (StatSoft, Tulsa, OK, USA). We plan to
perform intention-to-treat analyses. Continuous data
will be expressed as means with SDs or as medians
with ranges, whereas categorical variables will be
expressed as proportions. Normally distributed
continuous variables will be analysed using Student’s t
test, whereas the Wilcoxon rank-sum test will be used
for skewed data. Categorical variables will be analysed
using the chi-square test or Fisher’s exact test.
Confidence intervals (95% CIs) will be calculated for RR,
as well as risk differences for categorical variables,
and mean differences with 95% CIs will be calculated
for continuous variables.
The need for vit D supplementation in both term and
preterm infants is widely acknowledged [
multiple years of research and numerous publications,
there is still a lack of consensus regarding how much vit D
infants should receive and how long they should receive it.
Because 80% of calcium and phosphorus placental transfer
occurs between 24 and 40 weeks of gestation, preterm
infants are especially prone to adverse effects of vit D
insufficiency. A recent publication revealed that women
receiving hormonal contraceptives prior to conception are
at higher risk of decreased 25(OH)D levels, and this may
affect our results [
]. However, both inadequate and
excessive amounts of vit D may be unsafe and lead to
serious health issues. The results of our study may shed new
light on these concerns and contribute to optimising vit D
Recruitment started in May 2017 and will last until May
2019. Please see Table 1 and Fig. 2 for all planned
The manuscript, checklist and figures have been edited
according to Standard Protocol Items:
Recommendations for Interventional Trials (SPIRIT) guidelines [
(Additional file 1).
Additional file 1: SPIRIT 2013 Checklist: Recommended items to address
in a clinical trial protocol and related documents. (DOC 103 kb)
ABM: Average bone mass; ALP: Serum alkaline phosphatase;
BPD: Bronchopulmonary dysplasia; CA: Corrected age; DOL: Days of life;
ELBW: Extremely low birth weight; ESPGHAN: European Society for
Paediatric Gastroenterology, Hepatology and Nutrition; GA: Gestational
age; MBD: Metabolic bone disease; MR: Medical record; NEC: Necrotizing
enterocolitis; 25(OH)D: 25-Hydroxyvitamin D; P: Phosphate; PCA: Post-conceptional
age; RR: Relative risk; SAE: Serious adverse event; SOS: Speed of sound;
SPIRIT: Standard Protocol Items: Recommendations for Interventional
Trials; TRP: Tubular reabsorption of phosphate; US: Ultrasound;
VDD: Vitamin D deficiency; Vit D: Vitamin D
We thank Dr Agata Serwatowska-Bargieł and Dr Joanna Puskarz-Gąsowska for
their role in the choice and implementation of follow-up assessment.
No specific grant for this research was received from any funding agency in
the public, commercial or not-for-profit sector.
Availability of data and materials
The datasets generated and/or analysed during the present study are
available from the corresponding author on reasonable request.
AK conceptualized and designed the study, drafted the initial manuscript
and approved the final manuscript as submitted. MKBK critically reviewed
the manuscript and approved the final manuscript as submitted. JSS
conceptualized the study, reviewed and revised the manuscript, and
approved the final manuscript as submitted. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
The bioethics committee of the Medical University of Warsaw approved the
study (ethics approval and consent number KB143/2014 and amendment
number KB10/A/2016). We will obtain written informed consent from
participants prior to inclusion.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Holick MF. Vitamin D , deficiency. N Engl J Med . 2007 ; 357 : 266 - 81 .
2. Markestad T , Aksnes L , Ulstein M , Aarskog D . 25 - Hydroxyvitamin D and 1 ,25 -dihydroxyvitamin D of D2 and D3 origin in maternal and umbilical cord serum after vitamin D2 supplementation in human pregnancy . Am J Clin Nutr . 1984 ; 40 : 1057 - 63 .
3. Taylor SN , Wagner CL , Hollis BW . Vitamin D supplementation during lactation to support infant and mother . J Am Coll Nutr . 2008 ; 27 : 690 - 701 .
4. Hollis BW , Wagner CL . Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant . Am J Clin Nutr . 2004 ; 80 ( 6 Suppl) : 1752S - 8S .
5. Backstrom MC , Kuusela AL , Maki R . Metabolic bone disease of prematurity . Ann Med . 1996 ; 28 : 275 - 82 .
6. Dinlen N , Zenciroglu A , Beken S , Dursun A , Dilli D , Okumus N. Association of vitamin D deficiency with acute lower respiratory tract infections in newborns . J Matern Fetal Neonatal Med . 2016 ; 29 : 928 - 32 .
7. Grant CC , Kaur S , Waymouth E , Mitchell EA , Scragg R , Ekeroma A , Stewart A , Crane J , Trenholme A , Camargo Jr CA. Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomised controlled trial . Acta Paediatr . 2015 ; 104 : 396 - 404 .
8. Leis KS , McNally JD , Montgomery MR , Sankaran K , Karunanayake C , Rosenberg AM . Vitamin D intake in young children with acute lower respiratory infection [in Chinese] . Zhongguo Dang Dai Er Ke Za Zhi . 2012 ; 14 : 1 - 6 .
9. Maxwell CS , Carbone ET , Wood RJ . Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants . Nutr Rev . 2012 ; 70 : 548 - 52 .
10. Mimouni FB , Mandel D , Lubetzky R , Senterre T . Calcium, phosphorus, magnesium and vitamin D requirements of the preterm infant . World Rev Nutr Diet . 2014 ; 110 : 140 - 51 .
11. Abrams SA , Committee on Nutrition. Calcium and vitamin D requirements of enterally fed preterm infants . Pediatrics . 2013 ; 131 : e1676 - 83 .
12. Agostoni C , Buonocore G , Carnielli VP , De Curtis M , Darmaun D , Decsi T , Domellof M , Embleton ND , Fusch C , Genzel-Boroviczeny O , et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition . J Pediatr Gastroenterol Nutr . 2010 ; 50 : 85 - 91 .
13. Pludowski P , Karczmarewicz E , Bayer M , Carter G , Chlebna-Sokol D , CzechKowalska J , Debski R , Decsi T , Dobrzanska A , Franek E , et al. Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency . Endokrynol Pol . 2013 ; 64 : 319 - 27 .
14. Monangi N , Slaughter JL , Dawodu A , Smith C , Akinbi HT . Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay . Arch Dis Child Fetal Neonatal Ed . 2014 ; 99 : F166 - 8 .
15. Pinto K , Collins CT , Gibson RA , Andersen CC . Vitamin D in preterm infants: a prospective observational study . J Paediatr Child Health . 2015 ; 51 : 679 - 81 .
16. Natarajan CK , Sankar MJ , Agarwal R , Pratap OT , Jain V , Gupta N , Gupta AK , Deorari AK , Paul VK , Sreenivas V . Trial of daily vitamin D supplementation in preterm infants . Pediatrics . 2014 ; 133 : e628 - 34 .
17. Fort P , Salas AA , Ambalavanan N. Randomized clinical trial of vitamin D supplementation in extremely preterm infants [abstract 324] . J Investig Med . 2015 ; 63 : 417 .
18. Vogiatzi MG , Jacobson-Dickman E , DeBoer MD , Drugs, and Therapeutics Committee of the Pediatric Endocrine Society . Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature . J Clin Endocrinol Metab . 2014 ; 99 : 1132 - 41 .
19. Holick MF , Binkley NC , Bischoff-Ferrari HA , Gordon CM , Hanley DA , Heaney RP , Murad MH , Weaver CM , Endocrine Society . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2011 ; 96 : 1911 - 30 .
20. Ross AC , Manson JE , Abrams SA , Aloia JF , Brannon PM , Clinton SK , Durazo-Arvizu RA , Gallagher JC , Gallo RL , Jones G , et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know . J Clin Endocrinol Metab . 2011 ; 96 : 53 - 8 .
21. Nemet D , Dolfin T , Wolach B , Eliakim A . Quantitative ultrasound measurements of bone speed of sound in premature infants . Eur J Pediatr . 2001 ; 160 : 736 - 40 .
22. Rack B , Lochmuller EM , Janni W , Lipowsky G , Engelsberger I , Friese K , Kuster H . Ultrasound for the assessment of bone quality in preterm and term infants . J Perinatol . 2012 ; 32 : 218 - 26 .
23. Mercy J , Dillon B , Morris J , Emmerson AJ , Mughal MZ . Relationship of tibial speed of sound and lower limb length to nutrient intake in preterm infants . Arch Dis Child Fetal Neonatal Ed . 2007 ; 92 : F381 - 5 .
24. Viswanathan S , Khasawneh W , McNelis K , Dykstra C , Amstadt R , Super DM , Groh-Wargo S , Kumar D . Metabolic bone disease: a continued challenge in extremely low birth weight infants . JPEN J Parenter Enteral Nutr . 2014 ; 38 : 982 - 90 .
25. Aladangady N , Coen PG , White MP , Rae MD , Beattie TJ . Urinary excretion of calcium and phosphate in preterm infants . Pediatr Nephrol . 2004 ; 19 : 1225 - 31 .
26. Bastug F , Gunduz Z , Tulpar S , Poyrazoglu H , Dusunsel R. Urolithiasis in infants: evaluation of risk factors . World J Urol . 2013 ; 31 : 1117 - 22 .
27. Copelovitch L. Urolithiasis in children: medical approach . Pediatr Clin North Am . 2012 ; 59 : 881 - 96 .
28. Rustico SE , Calabria AC , Garber SJ . Metabolic bone disease of prematurity . J Clin Transl Endocrinol . 2014 ; 1 : 85 - 91 .
29. Schell-Feith EA , Holscher HC , Zonderland HM , Kist-Van Holthe JE , Conneman N , van Zwieten PH , Brand R , van der Heijden AJ. Ultrasonographic features of nephrocalcinosis in preterm neonates . Br J Radiol . 2000 ; 73 : 1185 - 91 .
30. Schell-Feith EA , Kist-van Holthe JE , van der Heijden AJ. Nephrocalcinosis in preterm neonates . Pediatr Nephrol . 2010 ; 25 : 221 - 30 .
31. Pilz S , Hahn A , Schön C , Wilhelm M , Obeid R . Effect of two different multimicronutrient supplements on vitamin D status in women of childbearing age: a randomized trial . Nutrients . 2017 ; 9 : 30 .
32. Chan AW , Tetzlaff JM , Altman DG , Dickersin K , Moher D. SPIRIT 2013 : new guidance for content of clinical trial protocols . Lancet . 2013 ; 381 : 91 - 2 .