https://orcid.org/0009-0003-1245-937X
Figures
Abstract
Background
Nutrition is vital for preterm infant development. Vitamins play key roles as cofactors and gene regulators for metabolic and immune functions and are common added components of preterm infant nutrition. However, information on how vitamins impact in-hospital and neurodevelopmental outcomes is sparse. We aimed to determine the effect of fat- and water-soluble vitamin supplementation on clinical outcomes during neonatal care and later neurodevelopment of very preterm (≤32 weeks’ gestation) and very low birth weight (≤1500 g) infants.
Methods and findings
4 databases and 3 clinical trial registries were systematically searched for randomised controlled trials (RCTs). Two reviewers independently extracted data and assessed quality using the Cochrane Risk of Bias tool. Meta-analyses were conducted using a random-effect model for each vitamin subgroup. Data are presented as risk ratios [95% confidence intervals]. Of 4074 references identified, 43 studies were included in the review. Only 2 reported neurodevelopment at 2 years, and only 4 were studies of water-soluble vitamins (vitamin C, 3 studies; B12 and folate, 1 study). Survival free from neurodisability was not affected by supplementation of vitamin A (0.89 [0.74–1.08], n = 538, very low certainty of evidence) or vitamin D (0.76 [0.46–1.27], n = 78, very low certainty of evidence). The incidence of bronchopulmonary dysplasia was decreased by vitamins D (0.58 [0.41–0.83]) and C (0.59 [0.37–0.93]), very low certainty of evidence), retinopathy of prematurity was decreased by vitamins A (0.77 [0.61–0.98]) and E (0.10 [0.01–0.80]), very low to low certainty of evidence) and intraventricular haemorrhage was decreased by vitamin E (0.70 [0.52–0.92], moderate certainty of evidence). Culture-proven sepsis was decreased by vitamin A (0.88 [0.77–0.99], moderate certainty of evidence).
Conclusions
There are few and inconclusive data on the effect of vitamin supplementation in preterm infants on later neurodevelopment. Evidence for shorter-term outcomes is mostly of low certainty. Together with substantial heterogeneity in trial design, it therefore is difficult to recommend a specific supplementation regimen.
Registry and Registry Number: This systematic review was prospectively registered on PROSPERO, ID CRD42023418552, available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023418552
Citation: Bronnert A, Bloomfield PM, Páramo LD, Lin L, Bloomfield FH, Cormack BE (2025) The effect of vitamin supplementation on neurodevelopmental and clinical outcomes in very low birth weight and very preterm infants: A systematic review and meta-analysis. PLoS One 20(7): e0327628. https://doi.org/10.1371/journal.pone.0327628
Editor: Fumihiko Namba,, Saitama Medical Center: Saitama Ika Daigaku Sogo Iryo Center, JAPAN
Received: September 13, 2024; Accepted: June 18, 2025; Published: July 9, 2025
Copyright: © 2025 Bronnert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BEC reports a relationship with Nestle Nutrition Institute and Nutricia Danone Australia Pty that includes board membership and speaking and lecture fees. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Abbreviations:: BPD, bronchopulmonary dysplasia; CI, confidence interval; ELBW, extremely low birth weight; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; IM, intramuscular; IVH, intraventricular haemorrhage; MD, mean difference; NEC, necrotizing enterocolitis; NNT, number needed to treat; RCT, randomized controlled trial; RD, risk difference; ROB, risk of bias; ROP, retinopathy of prematurity; RR, risk ratio; VLBW, very low birth weight; VP, very preterm.
Background
Healthy human pregnancies reach term at 37 to under 42 weeks. Infants born before term pregnancy are referred to as preterm. On average, preterm birth affects around 10% of global live births [1]. Of these, around 10% are born very preterm (VP) at less than 32 weeks of gestation, usually coinciding with a lower birth weight [2]. Neonatal care for very low birth weight (< 1500 g, VLBW) and VP infants has seen considerable achievements in recent decades. Survival rates have increased, as has survival free from major morbidity [2–4]. However, care for this most vulnerable group of infants remains challenging. Preterm birth means missing out on weeks or months of crucial growth processes in utero and entering the world with immature metabolic, immune, and organ development [5]. Incidence of neurodisability and sub-optimal health outcomes later in life are considerably higher than in full-term infants [4,6–10]. Neonatal complications, including increased inflammation and infection, contribute to compromised brain maturation alongside impaired nutrition [6]. VP infants are born in a state of malnutrition with little or no subcutaneous fat, glycogen, mineral, and vitamin stores. Adequate nutrition as soon as possible after birth is vital to maintain growth, support immune and metabolic function, and ensure optimal neurodevelopment [11,12]. However, the actual nutritional requirements of VP and VLBW infants are not known, especially their vitamin requirements.
Vitamins are essential nutrients that are required in small quantities but cannot be synthesised by the human body, either at all or in sufficient quantities. Provitamins are precursors that are converted to active compounds by metabolic processes in the body, such as the cleavage of beta-carotene to vitamin A. Vitamins may occur in various vitamers, similar forms with related functions, such as the various forms of tocopherols and tocotrienols of vitamin E. Active vitamins and their vitamers have diverse biochemical functions as co-factors for enzymatic reactions or regulators of gene expression in the energy metabolism and immune system. Therefore, deficiency can have serious to fatal consequences. The quantity of vitamins provided during neonatal intensive care, first through parenteral and later enteral nutrition, is based on estimations of requirements, and little is known about whether supplementation can improve development and clinical outcomes [11,13]. A recent systematic review of 27 guidelines on parenteral and enteral nutrition of preterm infants found the recommendations for fat- and water-soluble vitamin intake inconsistent and the evidence presented in the guidelines very weak. Intake recommendations vary between guidelines, and the recommended intake ranges for some vitamins are very wide [14]. The variation found in this systematic review of guidelines reflects the lack of conclusive research regarding dosages of vitamin supplementation and infants’ vitamin status that support improved health outcomes, leading to disparities in practice that may result in vitamin intake for preterm babies exceeding or falling short of their requirements [15].
Objective
We therefore undertook a systematic review to assess the effect of supplementation with any vitamin in VLBW and VP infants on survival free from neurodisability at 2 years or beyond, as well as its impact on growth, neonatal morbidities, and death before discharge from initial hospitalisation after birth.
Methods
This systematic review was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered prospectively in PROSPERO (registration number CRD42023418552).
Types of studies
Randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs were included. Cross-over RCTs were not included as their design is not suitable for measuring long-term outcomes. Abstracts that provided all necessary information were eligible for inclusion. Relevant ongoing and unpublished recent clinical trials were identified, and lead investigators were approached for data. Non-randomised trials were excluded.
Types of participants
Infants born at a VLBW (≤ 1500 g) or VP (≤ 32 weeks’ gestational age) of all sexes and ethnicities were included. While the World Health Organization’s definition of VLBW is < 1500 g [16], a slightly broader weight limit was chosen for this systematic review to account for different definitions chosen by study authors.
Intervention
Any interventional study that aimed to increase the intake of any fat-soluble or water-soluble vitamin or their respective provitamins, reporting on one or more of our primary or secondary outcome measures, was included. The route of administration could be enteral, intravenous, intramuscular, or a combination. The intervention could commence at any time during the initial hospitalisation after birth and be concluded at the time of discharge. We included studies that compared an intervention with a placebo, studies with two arms of interventions of the same type but with different doses, with or without a placebo arm, and studies that gave more than one of the relevant vitamins in combination as a multivitamin supplementation. Differences in the intervention were categorised as defined in the methods of the studies.
Standard feeding solutions for preterm infants usually include vitamins. This was not regarded as vitamin supplementation. Any extra vitamin administration on top of standard nutrition was regarded as supplementation. Studies in a wider population (e.g., all preterm births) that conducted subgroup analysis on the population of interest for this systematic review were eligible, provided the necessary subgroup data were available or could be provided by the authors upon request. We excluded studies that investigated the effect of supplementation after hospital discharge, studies that did not report on any clinical outcomes, and studies comparing different modes, timing, or designs of vitamin administration.
Outcome measures
Primary outcome.
The primary outcome was survival free from neurodisability at 2 years or beyond. Neurodisability was defined using, but not limited to, cognitive, language, and motor impairment, blindness, deafness, cerebral palsy, and measures of brain growth.
Secondary outcomes.
Secondary outcomes were components of primary outcomes, as well as neonatal morbidities, including retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) or chronic lung disease, necrotising enterocolitis (NEC), sepsis, anaemia of prematurity, growth measures, and death.
Subcategories were added for some outcomes to increase the precision of the analysis. ROP was split into all ROP and severe ROP, defined as ROP stage ≥3 or requiring treatment. IVH was split into all IVH and severe IVH, defined as IVH grades 3 and 4. Only studies that commenced supplementation within the first 24 hours after birth were included for this outcome, as onset of IVH after the first few days after birth is rare. For BPD, only data from studies that reported BPD as a need for oxygen at 28 days or 36 weeks postmenstrual age (PMA) or based on radiological requirements were included. If data for both time points were available, the 36-week timepoint was used for the meta-analysis. Other definitions, such as total days on ventilation, were not included. Sepsis was split into culture-proven sepsis only and proven and suspected sepsis combined.
Search methods and identification of studies
A search strategy was developed with a librarian to search the databases CENTRAL, Embase, Ovid MEDLINE, and CINAHL on 01.05.2023 and 02.05.2023. In addition, a search for registered trials was conducted on ClinicalTrials.gov, The WHO International Clinical Trials Registry Platform, and The Australian and New Zealand Clinical Trials Registry on the same dates. Searches were rerun on 14.12.2023 and 28.05.2024. The search strategies can be found in S1 File. The same strategy was used for all databases and registries; search terms and operators were adjusted where necessary.
Ongoing studies were identified and documented to evaluate for future inclusion in review updates. The search was not limited to any language or date of publication; however, only English search terms were used. Search terms accounted for both English and American spelling. In addition, all citations in the included studies were screened for publications that might have been missed in the search.
Data collection and analysis
Selection of studies.
All articles identified by the search strategy were imported into Covidence [17], a systematic review screening tool, to collect search results and remove duplicates. The titles and abstracts of all references were screened by two authors (AB and LDP) independently. The full text for all relevant studies was further evaluated according to the inclusion and exclusion criteria. Discrepancies were resolved by bilateral discussion first and, if necessary, with a third author (LL).
Data extraction and management.
All relevant data were extracted into a prespecified extraction spreadsheet, including administrative information, study methodology, outcome data, and information to assess the risk of bias. The extraction was completed by two authors independently (AB and PMB) and any discrepancies were discussed and resolved after completion. Quantitative data was entered into RevMan 5.4 [18] for meta-analysis.
Assessment of risk of bias.
All included studies were assessed for risk of bias (ROB) by two review authors (AB and PMB) independently using the Cochrane ROB 2 tool [19]. ROB 2 assesses the risk of bias on an outcome level. The risk of bias is assessed in five domains: randomisation and allocation concealment, deviations from the intended intervention, missing outcome data, outcome measurement, and reporting bias. All outcomes of the included studies were categorised into low risk of bias, high risk of bias, or some concerns.
Process for missing data.
In the case of important missing data, authors were contacted to obtain the necessary information. Authors of studies published before the year 2000 were not contacted. If no response was received, missing methodological data was reflected in the risk of bias assessment. If there was no relevant outcome data reported, the study was excluded.
Certainty of evidence.
The “Grading of Recommendations, Assessment, Development and Evaluation” (GRADE) [20] approach was used to assess the certainty of the evidence of the following outcomes: neurodevelopment and survival free of neurodisability at 2 years’ corrected age or beyond; diagnosis of ROP during initial hospitalisation after birth; diagnosis of IVH or other serious bleeding during initial hospitalisation after birth; diagnosis of BPD or chronic lung disease during initial hospitalisation after birth; diagnosis of NEC during initial hospitalisation after birth; diagnosis of sepsis during initial hospitalisation after birth; death during initial hospitalisation after birth.
This was assessed by two review authors (AB and PMB) independently. The certainty of evidence was summarised in a Summary of Findings Table based on the GRADEpro Guideline Development Tool.
Data analysis.
Data analysis was done using RevMan 5.4. Separate analyses were conducted to determine the effect of each single vitamin or vitamin combination. Due to considerable heterogeneity between the included studies regarding intervention, participants, and methodology, among other factors, if more than one study was included, a random-effects meta-analysis was used. Pre-specified subgroup analyses were conducted where data were available to explain heterogeneity in outcomes, as well as sensitivity analysis by excluding studies at high risk of bias.
For studies with more than two arms, the control or lowest dose group was split in two and double-entered into the meta-analysis to be compared with the remaining two groups. This was necessary to maintain the correct number of participants in the meta-analysis, as opposed to entering the full control group into the meta-analysis twice to be compared with both intervention arms.
Effect measures of outcomes
For dichotomous data, the number of outcome events in the control vs the intervention group was used to calculate risk ratios (RRs) and risk differences (RDs) with a 95% confidence interval (CI). If there was a statistically significant reduction or increase in the RD after the intervention, additional calculations were done for the number needed to treat (NNT) for an additional beneficial or harmful outcome. The mean difference (MD) with a 95% CI was calculated for continuous outcomes.
Assessment of heterogeneity.
The I2 statistic was used to quantify inconsistency among the included studies, and the Chi2 test was used to indicate whether any heterogeneity was significant (p < 0.1). Where substantial heterogeneity was detected, possible causes were explored by looking at methods and, if possible, conducting subgroup analyses.
Subgroup analysis
Subgroup analyses were planned for the following subgroups: extremely low birth weight (ELBW) ≤ 1000 g; extremely preterm (EP) ≤ 28 weeks; mode of administration of the supplementation: intravenous, intramuscular, enteral; supplementation regimen: e.g., daily, 3 times per week, single dose; ethnicity; country of birth: High and upper-middle-income countries vs. low and lower-middle-income countries according to the 2024 World Bank classification [21].
Results
Search results
Fig 1 shows the study screening and selection process. The search resulted in 4321 references, of which 1469 were automatically removed as duplicates by Covidence. After reviewing 2852 abstracts, 207 full-text references reporting on 170 studies were screened. An overview of reports resulting from the search and reasons for exclusion are presented in S1 Table. Articles not written in English were translated by native speakers. After screening the reference lists of included studies to identify missing records, 3 records were added manually (Hittner 1984 [22], Bental 1994 [23], and Schaffer 1988 [24]). This resulted in 76 references reporting on 43 studies included in the qualitative synthesis. Eighteen studies with 3350 infants investigated vitamin A supplementation; 5 studies with 387 infants, vitamin D; 14 studies with 1874 infants, vitamin E; 2 studies with 124 infants, vitamin K; 3 studies with 251 infants, vitamin C; and 1 study with 64 infants a combination of vitamin B12 and folate. The sample size per study ranged from 12 to 807 participants. Most studies (17) were conducted in the USA, 4 each in the UK and India, and a small number of studies in 13 other countries. Gale 1990 [25] did not report where the study was conducted. Ten studies reported on or provided subgroup data for ELBW infants, and 5 reported on EP infants. Half the reports were published before the year 2000, and 40% in the last 15 years (Tables 1–6).
ICTRP, International Clinical Trials Registry Platform; WHO, World Health Organization; ANZCTR, Australian New Zealand Clinical Trials Registry.
We identified 17 studies awaiting classification and 8 ongoing studies (S1 Table). Authors of studies that included a wider preterm population, i.e., not only VP and VLBW infants, were contacted, and subgroup data for VP and VLBW infants were requested. Authors of studies that continued supplementation after hospital discharge were contacted to provide outcome data at discharge. Authors of clinical trial registrations without a locatable publication of results were contacted for updates on the trial progress. If no responses were received, the studies were labelled as awaiting classification.
Risk of bias assessment
The risk of bias was assessed for 190 outcomes included in the meta-analysis and qualitative analysis (S2 Table). The risk of bias assessment for GRADE outcomes is summarised in Fig 2. The included studies were of variable methodological quality and rigour. Overall, 70 (37%) outcomes were found to be at high risk of bias, 84 (44%) at unclear risk of bias, and 36 (19%) at low risk of bias. Common reasons for the high or unclear risk of bias were lack of masking of staff, missing outcome data, inadequate description of data collection methods (e.g., time when an outcome was evaluated), and lack of published protocol or trial registration. If the study subjects were unmasked, but an adequate placebo was implemented (e.g., saline injections), the study was assessed as if the infants were masked. If no adequate placebo (e.g., sham injections) was implemented, the study was assessed as unmasked. All studies were assessed according to the intention-to-treat principle.
BPD, bronchopulmonary dysplasia; IVH, intraventricular haemorrhage; NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity.
Primary outcome
Two studies reported data for the primary outcome. Ambalavanan 2005 [55] (follow-up report of Tyson 1999 [52]) reported neurodevelopment at 18–22 months after vitamin A supplementation. Tyson 1999 investigated the effects of 5000 IU vitamin A given intramuscularly 3 times per week for the first 4 weeks after birth in ELBW infants. They reported neurodevelopment as a composite outcome of motor impairment (consisting of Bayley II Motor Development Index <70 or Psychomotor Development Index <70), cerebral palsy, complete blindness, or deafness (hearing aids in both ears). They found no effect of neonatal vitamin A supplementation on the composite outcome (RR 0.89 [0.74, 1.08], p = 0.24, n = 538, very low certainty of evidence) nor on the individual components (Cognitive impairment: RR 0.83 [0.66, 1.04], p = 0.11; Motor impairment: RR 0.83 [0.63, 1.10], p = 0.19; Blindness: RR 4.98 [0.24, 103.33], p = 0.30; Deafness RR 1.24 [0.34, 4.58],: p = 0.32; Cerebral palsy: RR 0.83 [0.57, 1.20], p = 0.22) at 18–22 months(Fig 3 and S1 Fig).
CI, confidence interval; M-H, Mantel-Haenszel method.
Salas 2018 [62] (follow-up report of Fort 2016 [61]) reported neurodevelopment at 22–26 months after vitamin D supplementation. Vitamin D was given in 3 different groups (no supplementation, daily 200 IU or daily 800 IU) through an orogastric tube during the first 4 weeks after birth. All infants received 200 IU daily in parenteral nutrition. They reported neurodevelopment as a composite outcome of Bayley III cognitive composite score <85, moderate or severe cerebral, hearing impairment, or visual impairment in both eyes and found no effect of neonatal vitamin D supplementation on the composite outcome (RR 0.76 [0.46, 1.27], p = 0.29, n = 78, 1 study, very low certainty of evidence) nor the component outcomes separately (Cognitive impairment: RR 0.84 [0.45, 1.58], p = 0.60; Language impairment: RR 0.80 [0.53, 1.21], p = 0.29), at 22–26 months (Fig 3 and S1 Fig).
Secondary outcomes
Studies investigating vitamins A, D, E, K, C, and a combination of vitamin B12 and folate reported data on the secondary outcomes. Data were available for all predefined outcomes. The results from the meta-analysis and the corresponding certainty of evidence assessments are summarised in Tables 7–12.
The evidence suggests vitamin A supplementation reduces the risk of ROP (RR 0.77 [0.61, 0.98], p = 0.03, NNT = 14, n = 1989, 11 studies, low certainty of evidence) and proven and suspected sepsis (RR 0.88 [0.78, 0.99], p = 0.04, NNT = 65, n = 2552, 8 studies, moderate certainty of evidence) (Fig 4). The 16 studies that contributed data to the quantitative analysis investigated a wide variety of enteral and intramuscular administration doses, duration, and regimens. Studies were conducted in 9 different countries, and 44% investigated or provided subgroup data for extremely preterm or extremely low birth weight infants.
CI, confidence interval; M-H, Mantel-Haenszel method.
The evidence suggests that vitamin A supplementation may result in little to no difference in severe ROP, all grade IVH, pulmonary haemorrhage, BPD, culture-proven sepsis, NEC, and mortality (Fig 4 and S1 Fig).
Vitamin D may reduce the risk of BPD (RR 0.58 [0.41, 0.83], p = 0.003, NNT = 7, n = 244, 3 studies, very low certainty of evidence) (Fig 5). 4 studies contributed data for the quantitative analysis. All studies investigated daily enteral administration of 200–2000 IU vitamin D daily for at least 4 weeks. They were conducted in 3 different countries; one study investigated extremely preterm infants.
CI, confidence interval; M-H, Mantel-Haenszel method.
Vitamin D may have little to no effect on any stage or severe ROP, any grade or severe IVH, NEC, culture-proven sepsis, and mortality, but the evidence is very uncertain (S1 Fig).
The evidence suggests vitamin E supplementation reduces the risk of severe ROP (RR 0.10 [0.01, 0.80], p = 0.03, NNT = 12, n = 200, 2 studies, very low certainty of evidence) and any grade IVH (RR 0.70 [0.52, 0.92], p = 0.01, NNT = 12, n = 1330, 9 studies, moderate certainty of evidence) (Fig 6). Eleven studies contributed data for the quantitative analysis. They investigated a wide variety of enteral, intravenous, and intramuscular administration doses, duration, and regimens. Studies were conducted in 5 different countries; for one study, the location was not clear. About half of the studies investigated or provided subgroup data on extremely low birth weight infants.
CI, confidence interval; M-H, Mantel-Haenszel method.
The evidence suggests that vitamin E supplementation may result in little to no difference in any stage ROP, severe IVH, BPD, NEC, culture-proven or suspected sepsis, and mortality (Fig 6 and S1 Fig).
Two studies were included for vitamin K. Sethi 2019 [92] included 80 neonates of any gestational age, but authors were contacted and provided data for the 49 participants born < 33 weeks of gestation. All infants in the two trials received intramuscular vitamin K of varying dosages. The evidence is very uncertain on the effect of different doses of vitamin K on any grade IVH, pulmonary haemorrhage, NEC, mortality, and a compound outcome of any type of clinical bleed defined by the authors (S1 Fig).
Vitamin C may reduce the risk of BPD (RR 0.59 [0.37, 0.93], p = 0.02, NNT = 6, n = 160, 2 studies, very low certainty of evidence) (Fig 5). Three studies contributed data for the quantitative analysis, investigating daily enteral or intravenous administration of 30–100 mg.kg-1 for one to 4 weeks. Studies were conducted in 2 different countries, and no studies investigated only extremely low birth weight or extremely preterm infants.
Vitamin C may have little to no effect on any stage ROP, any grade or severe IVH, NEC, culture-proven sepsis, and mortality but the evidence is very uncertain (S1 Fig).
One study investigated a combination of vitamin B12 and folate supplementation. There were no differences between the supplemented and comparator groups in NEC, and mortality (S1 Fig).
Despite considerable heterogeneity in the methods of the included studies, especially regarding the mode and dose of vitamin supplementation, no statistical heterogeneity was detected in the data.
If meta-analysis of data was not possible, or studies provided data narratively, results were synthesised qualitatively in the S2 File. This includes studies reporting on the effects of supplementation on anaemia and growth outcomes.
Sensitivity analysis
After exclusion of studies at high risk of bias for the outcome, there were no effects of vitamin A on ROP (RR 0.80 [0.58, 1.10], p = 0.17, n = 1393, n of studies removed = 5, n of studies remaining = 6). Similarly, vitamin E did not affect severe ROP (RR 0.12 [0.01, 2.13], p = 0.15, n = 99, n of studies removed = 1, n of studies remaining = 1), and vitamin C did not affect BPD (RR 0.57 [0.25, 1.28], p = 0.17, n = 47, n of studies removed = 1, n of studies remaining = 1).
Subgroup analysis
Subgroup analyses could not be conducted for the primary outcome as only one study contributed data for vitamin A and D supplementation, respectively. Subgroup analyses by ethnicity were planned but could not be conducted due to a lack of data. Details on all conducted subgroup analyses can be found in S3 Table.
Birth weight and gestational age at birth.
Vitamin A supplementation showed no effect when only ELBW infants (up to 1081 infants) were included in the meta-analysis. Vitamin A supplementation decreased the risk of ROP for EP infants (RR 0.63 [0.49, 0.81], p < 0.001, n = 450, 2 studies).
For vitamin E, the subgroup analysis with only ELBW infants showed an increased risk of sepsis after supplementation (RR 1.76 [1.04, 2.99], p = 0.04, n = 291, 2 studies). The decreased risk of IVH persisted in ELBW infants (RR 0.70 [0.50, 0.98], p = 0.04, n = 349, 4 studies).
Mode of administration and regimen.
Only intramuscular, but not enteral vitamin A reduced the risk of BPD (RR 0.84 [0.74, 0.95], p = 0.006, n = 1033, 7 studies) and culture-proven sepsis (RR 0.85 [0.74, 0.98], p = 0.03, n = 1067, 4 studies) (S3 Table). In subgroup analyses of the administration regimen, alternate day intramuscular injections for 8 doses over 15 days reduced the risk of severe IVH, but only one study with 47 participants was included in the subgroup (RR 0.26 [0.08, 0.81], p = 0.02). Administration 3 times per week for 2–4 weeks was also shown to decrease the risk of BPD (RR 0.86 [0.75, 0.98], p = 0.03, n = 909, 4 studies, all intramuscular administration) but showed no significance for intramuscular administration on alternate days for 2–6 weeks, or for 3 doses in the first week after birth. There was no evidence of an interaction between different modes of administration and the effects of vitamins on outcomes.
Similarly, for vitamin E, there were no effects for studies investigating enteral or intravenous administration, but intramuscular administration reduced the risk of IVH (RR 0.58 [0.46, 0.73], p < 0.001, n = 513, 4 studies) (S3 Table). One study used a mixed administration approach, giving vitamin E intravenously while the infants were on intravenous fluids and enterally when enteral feeds were established, continuously monitoring serum vitamin E concentrations, and adjusting the dose to maintain a target concentration of 5 mg.dL-1. Intramuscular injections were used when enteral vitamin E did not successfully increase serum concentrations to the target. This approach increased the risk of culture-proven sepsis in the intervention group (RR 1.82 [1.18, 2.80], p = 0.007, n = 545, 1 study) (S3 Table). For the supplementation regimen, a regimen of intramuscular injections on days 1, 2, 4, and 6 after birth reduced the risk of IVH (RR 0.61 [0.41, 0.90], p = 0.01, n = 271, 2 studies) (S3 Table). Interaction tests demonstrated no subgroup differences between different modes of administration or administration regimens.
Country of birth.
86% of studies were conducted in high or upper-middle-income countries, 12% in lower-middle-income countries, and none in low-income countries. In one study, the country was not stated (Gale 1990 [25]).
Subgroup analysis was possible for vitamin A and vitamin E. Vitamin A supplementation reduced the risk of proven and suspected sepsis (RR 0.84 [0.74, 0.96], p = 0.01, n = 1517, 6 studies) in high and upper-middle-income countries. Vitamin E reduced the risk of IVH (RR 0.71 [0.53, 0.96], p = 0.03, n = 1242, 7 studies) and increased the risk of proven sepsis (RR 1.37 [1.01, 1.86], p = 0.04, n = 955, 5 studies) in high and upper-middle-income countries (S3 Table). Interaction tests demonstrated no subgroup differences between groups for either vitamin supplementation.
Discussion
This systematic review included 43 studies investigating vitamin supplementation to reduce mortality and morbidities in 6096 VP and VLBW infants. We found very little evidence on the effects of vitamin supplementation during the neonatal period for this population on neurodevelopmental outcome at 2 years: only 2 studies reported follow-up at 2 years after neonatal vitamin A and vitamin D supplementation and found no effects.
However, supplementation with some vitamins may decrease the risk of neonatal morbidities during the initial hospital stay after birth. Vitamin A supplementation reduced the risk of ROP and sepsis, but not of BPD. These findings differ from a recent systematic review and meta-analysis on vitamin A supplementation in VLBW and VP infants, where vitamin A was shown to have beneficial effects on the risk of BPD at 36 weeks and any stage ROP but not sepsis [46]. Due to differences in inclusion criteria, two trials included in the previous review were not included in our review because supplementation was continued post-discharge, and two included in our review were not included in the former. In addition, one large trial (Meyer 2024 [38]) has been published since the previous review. Vitamin A has been shown to promote pulmonary epithelial cell growth, development, and differentiation and promote surfactant synthesis in the preterm infant [97,98]. Retinal, a vitamer of vitamin A, is a building block for photoreceptors in the human eye and is thus important for the development of vision [97]. Furthermore, vitamin A regulates mucosal immunity and immune response [99]. It has been suggested that immaturity of the preterm infant’s gastrointestinal tract leads to impaired intestinal absorption of fat-soluble vitamin formulations and that injections may be necessary to show any effect [100]. Our subgroup analyses showed that only intramuscular vitamin A reduced the risk of BPD and culture-proven sepsis, while there were no effects in a subgroup of enteral supplementation.
Even though vitamin D supplementation was shown to reduce the risk of BPD, only 3 studies and 244 infants were included. Additionally, 2 of the 3 studies were at high risk of bias, leading to the assessment that the evidence for this finding is very uncertain. Vitamin D is crucial for regulating calcium-phosphate metabolism, provided the intake of these minerals is adequate [101]. Vitamin D has recently been associated with immunity and inflammation regulation, binding to vitamin D receptor on cells of the innate and adaptive immune system [102–104]. BPD is at least partially an inflammatory disease, so modulation of the immune response through vitamin D supplementation is feasible and warrants further research.
Vitamin E reduced the risk of severe ROP, but only 2 studies were included with some concerns or high risk of bias and very low certainty of evidence. However, vitamin E was also shown to reduce the risk of any grade IVH with moderate certainty of evidence. Vitamin E has a strong antioxidative function, neutralising free radicals and protecting DNA, proteins, and lipids from oxidative damage. Oxidative stress and increased inflammation are prevalent in preterm infants and are contributing factors to the development of several preterm complications [105]. Meanwhile, excess intravenous vitamin E supplementation may have adverse effects, potentially increasing the risk of sepsis and haemorrhage [106]. We found that sepsis was slightly increased by vitamin E, with low certainty of evidence. However, this finding was not statistically significant.
Our review found no effects of additional vitamin K supplementation, likely explained by the small number of included studies and participants (2 studies, 170 infants). Vitamin K is mostly important in the context of vitamin K deficiency bleeding [107]. Administration of a single intramuscular 1 mg dose of vitamin K for all newborns shortly after birth, regardless of the gestational age or size, is universal clinical practice and the most effective prevention of deficiency-related bleeding [108]. One of the studies in this review investigated alternative doses to the 1 mg dose and found no differences between a 0.3 mg, 0.5 mg, and 1 mg dose [90]. The second study investigated whether additional vitamin K after prolonged antibiotic treatment can prevent antibiotic-related vitamin K deficiency bleeding and found no differences between groups [92].
Vitamin C was shown to reduce the risk of BPD, based on 2 studies including 160 infants, one at high risk of bias, and thus assessed as very low certainty of evidence. Vitamin C has an antioxidant function and aids in regulating inflammation [93].
Besides the 3 studies with few participants investigating vitamin C, we found very little evidence on water-soluble vitamins. One study investigated a combination of vitamin B12 and folate supplementation for 4 weeks, finding no effects on NEC, or death in infants born weighing ≤1300 g [96].
Little is known about the status and requirements of water-soluble vitamins in preterm infants. Emerging research points to thiamine as a key nutrient to sustain an adequate growth rate without the risk of lactic acidosis or refeeding syndrome [109–114]. The immaturity of metabolic processes in preterm infants leads to insufficient conversion from nutritive to the bioactive form of vitamins as has been suggested for the conversion from inactive vitamin B6 vitamers [115] or decreased activity of vitamin-dependent enzymes such as biotin-dependent carboxylases [116]. The biochemical mechanisms of other vitamins, such as folate and vitamin B12, are intertwined [117,118].
We implemented rigorous methods for this systematic review, leading to a comprehensive and robust overview and evaluation of data, using GRADE to assess the certainty of included evidence. We published a protocol before the inception of the search, detailing the rationale and objective. Any deviations from the protocol were justified and reported. Collecting data on every vitamin supplementation identified important gaps in the evidence regarding the nutritional care for VP and VLBW infants. Few studies were available for vitamins C, B12, and folate, and none for other water-soluble vitamins. We also demonstrate a lack of up-to-date evidence on this topic, with half of the included studies published in the 1980s or 1990s, when neonatal care and nutrition were very different.
Included studies used different modes of administration (intramuscular injections, enteral, or intravenous) or a combination. The duration of vitamin supplementation ranged from a single dose to more than 8 weeks, with different regimens such as daily, weekly, or alternating days. Supplementation doses varied widely, and some infants received varying amounts of routine vitamin supplementation as standard nutrition, in addition to the vitamin intervention. This variability presents a substantial challenge in deriving clinical practice recommendations from the findings of our meta-analysis. Many outcomes were inadequately powered, with very few studies and participants included, which may lead to false-positive results. Due to the diversity of participant characteristics and differences in inclusion criteria such as gestational age at birth, weight, age at recruitment, or health status at recruitment, limited individual treatment recommendations can be made from the findings. The certainty of evidence was evaluated as very low for most (76%) outcomes due to inadequate sample size, representativeness of the included studies for the outcome (indirectness), and high risk of bias. Many older studies lack stringency in methodology and reporting to the current scientific standard, reflected in their higher risk of bias assessment.
Even though additional supplementation, especially with vitamins A and E, has been shown to prevent some short-term morbidities, there is little evidence of long-term benefits. Vitamin supplementation, especially intravenous or intramuscular administration of fat-soluble vitamins, is not without risks, and over-supply may have adverse effects. While older studies lack scientific rigour, the methodology of more recent randomised controlled trials is also heterogeneous, making it almost impossible to recommend a specific supplement dose or regimen based on this systematic review.
Supporting information
S2 File. Narrative synthesis of studies not included in the meta-analysis.
https://doi.org/10.1371/journal.pone.0327628.s002
(DOCX)
S1 Table. All reports identified in the search.
Including bibliographic information and reason for exclusion.
https://doi.org/10.1371/journal.pone.0327628.s003
(XLSX)
S2 Table. Complete Cochrane Risk of Bias 2 assessment.
https://doi.org/10.1371/journal.pone.0327628.s004
(XLSX)
S3 Table. Table of subgroup analysis.
Data are presented as risk ratios [95% confidence interval]. Bold and shaded cells indicate statistical significance. Cells with no data indicate no subgroup analysis was possible. BPD, bronchopulmonary dysplasia; ELBW, extremely low birth weight; IM, intramuscular; IVH, intraventricular haemorrhage; NEC, necrotising enterocolitis; ROP, retinopathy of prematurity.
https://doi.org/10.1371/journal.pone.0327628.s005
(XLSX)
S4 Table. Consensus data extraction form.
Both reviewers (AB and PMB) extracted data in respective extraction forms independently from September to October 2023. Extracted data were compared, discrepancies discussed, and data were entered into a consensus form. Data from the consensus form were entered into RevMan 5.4 for meta-analysis.
https://doi.org/10.1371/journal.pone.0327628.s006
(XLSX)
Acknowledgments
Authors’ responsibilities: AB, BEC, FHB, and LL conceptualised the research; AB created the search strategy and conducted the literature search; AB and LDP screened eligible studies; AB and PMB conducted the data extraction, ROB evaluation, and GRADE; AB conducted the data analysis and wrote the manuscript; LL provided guidance during all stages; all authors contributed to the data interpretation and final draft of the manuscript, and have read and approved the final manuscript.
References
- 1.
Born too soon: decade of action on preterm birth. Geneva: World Health Organization. 2023. Available from: https://www.who.int/publications/i/item/9789240073890
- 2. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller A-B, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):2162–72. pmid:22682464
- 3. Zayegh AM, Doyle LW, Boland RA, Mainzer R, Spittle AJ, Roberts G, et al. Trends in survival, perinatal morbidities and two-year neurodevelopmental outcomes in extremely low-birthweight infants over four decades. Paediatr Perinat Epidemiol. 2022;36(5):594–602. pmid:35437828
- 4. Moore T, Hennessy EM, Myles J, Johnson SJ, Draper ES, Costeloe KL, et al. Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. BMJ. 2012;345(dec04 3):e7961.
- 5. Patel RM. Short- and Long-Term Outcomes for Extremely Preterm Infants. Am J Perinatol. 2016;33(3):318–28. pmid:26799967
- 6. Volpe JJ. Dysmaturation of Premature Brain: Importance, Cellular Mechanisms, and Potential Interventions. Pediatr Neurol. 2019;95:42–66. pmid:30975474
- 7. Adams-Chapman I, Heyne RJ, DeMauro SB, Duncan AF, Hintz SR, Pappas A, et al. Neurodevelopmental Impairment Among Extremely Preterm Infants in the Neonatal Research Network. Pediatrics. 2018;141(5):e20173091. pmid:29666163
- 8. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-Analysis of Neurobehavioral Outcomes in Very Preterm and/or Very Low Birth Weight Children. Pediatrics. 2009;124(2):717–28.
- 9. Larroque B, Ancel P-Y, Marret S, Marchand L, André M, Arnaud C, et al. Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet. 2008;371(9615):813–20. pmid:18328928
- 10. Crump C. An overview of adult health outcomes after preterm birth. Early Hum Dev. 2020;150:105187. pmid:32948365
- 11. Rizzo V, Capozza M, Panza R, Laforgia N, Baldassarre ME. Macronutrients and Micronutrients in Parenteral Nutrition for Preterm Newborns: A Narrative Review. Nutrients. 2022;14(7):1530. pmid:35406142
- 12. Skinner AM, Narchi H. Preterm nutrition and neurodevelopmental outcomes. World J Methodol. 2021;11(6):278–93. pmid:34888181
- 13. Embleton ND, Jennifer Moltu S, Lapillonne A, van den Akker CHP, Carnielli V, Fusch C, et al. Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts. J Pediatr Gastroenterol Nutr. 2023;76(2):248–68. pmid:36705703
- 14. Meiliana M, Alexander T, Bloomfield FH, Cormack BE, Harding JE, Walsh O, et al. Nutrition guidelines for preterm infants: A systematic review. JPEN J Parenter Enteral Nutr. 2024;48(1):11–26. pmid:37855274
- 15. Oliver C, Watson C, Crowley E, Gilroy M, Page D, Weber K, et al. Vitamin and Mineral Supplementation Practices in Preterm Infants: A Survey of Australian and New Zealand Neonatal Intensive and Special Care Units. Nutrients. 2019;12(1):51. pmid:31878077
- 16.
WHO recommendations for care of the preterm or low birth weight infant. Geneva: World Health Organization. 2022. Availble from: https://www.who.int/publications/i/item/9789240058262
- 17.
Covidence systematic review software. Melbourne, Australia: Veritas Health Innovation.
- 18.
Review manager 5 (RevMan 5). Copenhagen: The Cochrane Collaboration. 2020.
- 19.
Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Assessing risk of bias in a randomized trial. Cochrane Handbook for Systematic Reviews of Interventions. 6.3 edition. Cochrane. 2022.
- 20.
Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE Handbook. [place unknown]: GRADE Working Group. 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html
- 21. World Bank Country and Lending Groups: World Bank. 2024 [cited 2024 01/02]. Available from: https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups.
- 22. Hittner HM, Rudolph AJ, Kretzer FL. Suppression of severe retinopathy of prematurity with vitamin E supplementation. Ultrastructural mechanism of clinical efficacy. Ophthalmology. 1984;91(12):1512–23. pmid:6395059
- 23. Bental R, Cooper P, Cummins R, Sandler D, Wainer S, Rotschild A. Vitamin A therapy - effects on the incidence of bronchopulmonary dysplasia. South African Journal of Food Science and Nutrition. 1994;6(4):141–5.
- 24. Schaffer DB, Johnson L, Quinn GE, Abbasi S, Otis C, Bowen FW. Vitamin E and retinopathy of prematurity: the ophthalmologist’s perspective. Birth Defects Orig Artic Ser. 1988;24(1):219–35. pmid:3179413
- 25. Gale R, Vreman HJ, Ferguson JE, Stevenson DK. Vitamin E and CNS hemorrhage in premature infants. Pediatric Reviews and Communications. 1990;4:231–324.
- 26. Ambalavanan N, Wu T-J, Tyson JE, Kennedy KA, Roane C, Carlo WA. A comparison of three vitamin A dosing regimens in extremely-low-birth-weight infants. J Pediatr. 2003;142(6):656–61. pmid:12838194
- 27. Bental R, Cooper P, Sandler D, Wainer S. The effects of vitamin A therapy on the incidence of chronic lung disease in premature infants (abstract). Pediatric Research. 1990;27:296.
- 28. Calisici E, Yarci E, Degirmencioglu H, Oncel M, Oguz S, Uras N, et al. PO-0731 The Effects Of Early Oral Vitamin A Treatment On The Prevention Of Bronchopulmonary Displasia In The Low Birth Weight Infants. Arch Dis Child. 2014;99(Suppl 2):A494.3–A494.
- 29. Giridhar S, Kumar J, Attri SV, Dutta S, Kumar P. Intramuscular followed by oral vitamin A supplementation in neonates with birth weight from 750 to 1250 g: a randomized controlled trial. Indian Journal of Clinical Biochemistry. 2020;35(2):197–204.
- 30. Kiatchoosakun P, Jirapradittha J, Panthongviriyakul MC, Khampitak T, Yongvanit P, Boonsiri P. Vitamin A supplementation for prevention of bronchopulmonary dysplasia in very-low-birth-weight premature Thai infants: a randomized trial. J Med Assoc Thai. 2014;97 Suppl 10:S82–8. pmid:25816542
- 31. Koo WW, Krug-Wispe S, Succop P, Tsang RC, Neylan M. Effect of different vitamin A intakes on very-low-birth-weight infants. Am J Clin Nutr. 1995;62(6):1216–20. pmid:7491883
- 32. Mactier H, McCulloch DL, Hamilton R, Galloway P, Bradnam MS, Young D, et al. Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity. J Pediatr. 2012;160(6):954-9.e1. pmid:22284923
- 33. Hamilton R, Mactier H, Farrell L, Young D, McCulloch DL, Bradnam MS, et al. ERGs show increased retinal sensitivity following highdose vitamin A supplementation of very low birthweight infants: the VitAL study. Documenta Ophthalmologica. 2010;121:3–4.
- 34. Mactier H, Hamilton R, McCulloch DL, Farrell L, Young D, Galloway P, et al. Additional early vitamin a supplementation in infants at risk of retinopathy of prematurity (ROP): Effect upon body stores of vitamin a and retinal function at 36 weeks’ postmenstrual age (PMA). Journal of Pediatric Gastroenterology & Nutrition. 2011;52(Suppl 1):E86.
- 35. McCulloch DL, Mactier H, Farrell L, Hamilton R. Light-adapted ERGs in the VitAL study: A randomised controlled trial of early high-dose vitamin A in infants at risk of retinopathy of prematurity (ROP). Documenta Ophthalmologica. 2012;124:22–3.
- 36. EUCTR2005-003402-29-GB. Does additional vitamin A supplementation improve retinal function and conjunctival health in very low birth weight infants? - vitamin A and retinal function in low birth weight infants. 2005. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-003402-29/results
- 37. NCT00417404. Vitamin A and very low birthweight babies (VitAL). 2006. Available from: https://clinicaltrials.gov/study/NCT00417404
- 38. Meyer S, Bay J, Franz AR, Ehrhardt H, Klein L, Petzinger J, et al. Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial. Lancet Respir Med. 2024;12(7):544–55. pmid:38643780
- 39. Meyer S, Gortner L, NeoVitaA Trial investigators. Up-date on the NeoVitaA Trial: Obstacles, challenges, perspectives, and local experiences. Wien Med Wochenschr. 2017;167(11–12):264–70. pmid:27671007
- 40. Meyer S, NeoVitA SG. P007 - Interim Report: NeoVitaA Study Trial. Monatsschrift Kinderheilkunde. 2016;164(2):156.
- 41. Meyer S, Gortner L, NeoVitaA Trial Investigators. Early postnatal additional high-dose oral vitamin A supplementation versus placebo for 28 days for preventing bronchopulmonary dysplasia or death in extremely low birth weight infants. Neonatology. 2014;105(3):182–8. pmid:24434948
- 42. DRKS00006541. A prospective, multicenter, double blind, placebo-controlled, two-arm parallel group phase 3 trial to evaluate the effect of early postnatal additional high dose oral vitamin A supplementation of 5000 IU/kg/d versus placebo for 28 days for preventing bronchopulmonary dysplasia (BPD) or death in extremely-low-birth-weight (ELBW) infants. 2014. Available from: https://drks.de/search/en/trial/DRKS00006541
- 43. EUCTR2013-001998-24-DE. A prospective, multicenter, double blind, placebo-controlled, two-arm parallel group phase 3 trial to evaluate the effect of early postnatal additional high dose oral vitamin A supplementation of 5000 IU/kg/d versus placebo for 28 days for preventing bronchopulmonary dysplasia (BPD) or death in extremely-low-birth-weight (ELBW) infants. 2014. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-001998-24/DE
- 44. Papagaroufalis C, Megreli C, Hagjigeorgi C, Xanthou M. A trial of vitamin A supplementation for the prevention of intraventricular hemorrhage in very low birth weight neonates. J Perinat Med. 1991;19 Suppl 1:382–7. pmid:1779392
- 45. Papagaroufalis C, Spyropoulos G, Stamocosta E, Megreli CH, Xanthou M. Effect of Vitamin A (VA) supplementation on Retinopathy Of Prematurity (ROP) in Very Low Birth Weight (VLBW) infants. Pediatr Res. 1992;32(5):617–617.
- 46. Rakshasbhuvankar AA, Pillow JJ, Simmer KN, Patole SK. Vitamin A supplementation in very-preterm or very-low-birth-weight infants to prevent morbidity and mortality: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2021;114(6):2084–96. pmid:34582542
- 47. Rakshasbhuvankar A, Patole S, Simmer K, Pillow JJ. Enteral vitamin A for reducing severity of bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled trial. BMC Pediatr. 2017;17(1):204. pmid:29246130
- 48. Ravishankar C, Nafday S, Green RS, Kamenir S, Lorber R, Stacewicz-Sapuntzakis M, et al. A trial of vitamin A therapy to facilitate ductal closure in premature infants. J Pediatr. 2003;143(5):644–8. pmid:14615738
- 49. Schwarz KB, Cox JM, Sharma S, Clement L, Humphrey J, Gleason C, et al. Possible antioxidant effect of vitamin A supplementation in premature infants. J Pediatr Gastroenterol Nutr. 1997;25(4):408–14. pmid:9327371
- 50. Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr. 1987;111(2):269–77. pmid:3302193
- 51. Sun H, Cheng R, Wang Z. Early vitamin A supplementation improves the outcome of retinopathy of prematurity in extremely preterm infants. Retina. 2020;40(6):1176–84. pmid:30964778
- 52. Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, et al. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999;340(25):1962–8. pmid:10379020
- 53. Kennedy KA, Stoll BJ, Ehrenkranz RA, Oh W, Wright LL, Stevenson DK, et al. Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network. Early Hum Dev. 1997;49(1):19–31. pmid:9179535
- 54. Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA. Vitamin A supplementation for extremely-low-birth-weight infants. Journal of Pediatrics. 2000;136(1):124–5.
- 55. Ambalavanan N, Tyson JE, Kennedy KA, Hansen NI, Vohr BR, Wright LL, et al. Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months. Pediatrics. 2005;115(3):e249-54. pmid:15713907
- 56. NCT01203488. Vitamin A supplementation for extremely-low-birth-weight infants. 1996. Available from: https://classic.clinicaltrials.gov/show/NCT01203488
- 57. Wardle SP, Hughes A, Chen S, Shaw NJ. Randomised controlled trial of oral vitamin A supplementation in preterm infants to prevent chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2001;84(1):F9–13. pmid:11124916
- 58. Anderson-Berry A, Thoene M, Wagner J, Lyden E, Jones G, Kaufmann M, et al. Randomized trial of two doses of vitamin D3 in preterm infants <32 weeks: Dose impact on achieving desired serum 25(OH)D3 in a NICU population. PLoS One. 2017;12(10):e0185950. pmid:29016653
- 59.
Hanson C, Lyden E, Thoene M, Wagner J, Anderson-Berry A. Vitamin D supplementation and NICU outcomes in premature infants. Pediatric academic societies annual meeting; 2014 July 17-18; Vienna, Austria. 2014.
- 60. Evans JR, Allen AC, Stinson DA, Hamilton DC, St John Brown B, Vincer MJ, et al. Effect of high-dose vitamin D supplementation on radiographically detectable bone disease of very low birth weight infants. J Pediatr. 1989;115(5 Pt 1):779–86. pmid:2809913
- 61. Fort P, Salas AA, Nicola T, Craig CM, Carlo WA, Ambalavanan N. A Comparison of 3 Vitamin D Dosing Regimens in Extremely Preterm Infants: A Randomized Controlled Trial. J Pediatr. 2016;174:132-138.e1. pmid:27079965
- 62. Salas AA, Woodfin T, Phillips V, Peralta-Carcelen M, Carlo WA, Ambalavanan N. Dose-Response Effects of Early Vitamin D Supplementation on Neurodevelopmental and Respiratory Outcomes of Extremely Preterm Infants at 2 Years of Age: A Randomized Trial. Neonatology. 2018;113(3):256–62. pmid:29393233
- 63. Craig C, Ambalavanan N, McNair T. Early vitamin d supplementation for prevention of respiratory morbidity in extremely preterm infants. Journal of Investigative Medicine. 2014;62(2):492.
- 64. Aristizabal N, Holder MP, Durham L, Ashraf AP, Taylor S, Salas AA. Safety and Efficacy of Early Vitamin D Supplementation in Critically Ill Extremely Preterm Infants: An Ancillary Study of a Randomized Trial. J Acad Nutr Diet. 2023;123(1):87–94. pmid:35728797
- 65. Ge H, Qiao Y, Ge J, Li J, Hu K, Chen X, et al. Effects of early vitamin D supplementation on the prevention of bronchopulmonary dysplasia in preterm infants. Pediatr Pulmonol. 2022;57(4):1015–21. pmid:34989171
- 66. Koo WW, Krug-Wispe S, Neylan M, Succop P, Oestreich AE, Tsang RC. Effect of three levels of vitamin D intake in preterm infants receiving high mineral-containing milk. J Pediatr Gastroenterol Nutr. 1995;21(2):182–9. pmid:7472905
- 67. Barekatain B, Saraeian S, Farghadani M, Armanian AM, Shahsanaee A, Rouhani E, et al. Effect of Vitamin E in Prevention of Intraventricular Hemorrhage in Preterm Neonates. Int J Prev Med. 2018;9:97. pmid:30534353
- 68. Barekatain B, Armanian AM, Farghadani M, Safaei A, Shahsanai AD, Saraeian S. Evaluation of the effects of vitamin E on prematurity complications in premature neonates. Journal of Isfahan Medical School. 2017;35(446):1185–91.
- 69. IRCT2015042521910N2. Evaluation of effect of vitamin E in prevention of intraventricular hemorrhage in preterm neonates with gestational age below 30 weeks in Alzahra Hospital. 2017. Available from: https://www.irct.ir/trial/19052
- 70. Bell EF, Hansen NI, Brion LP, Ehrenkranz RA, Kennedy KA, Walsh MC, et al. Serum Tocopherol Levels in Very Preterm Infants After a Single Dose of Vitamin E at Birth. Pediatrics. 2013;132(6):e1626–33.
- 71. Chiswick ML, Johnson M, Woodhall C, Gowland M, Davies J, Toner N, et al. Protective effect of vitamin E (DL-alpha-tocopherol) against intraventricular haemorrhage in premature babies. Br Med J (Clin Res Ed). 1983;287(6385):81–4. pmid:6407714
- 72. Finer NN, Schindler RF, Grant G, Hill GB, Peters K. Effect of intramuscular vitamin E on frequency and severity of retrolental fibroplasia. A controlled trial. Lancet. 1982;1(8281):1087–91. pmid:6122890
- 73. Finer NN, Peters KL, Schindler RF, Grant GD. Vitamin E and retrolental fibroplasia: prevention of serious ocular sequelae. Ciba Found Symp. 1983;101:147–64. pmid:6360586
- 74. Finer NN, Schindler RF, Peters KL, Grant GD. Vitamin E and retrolental fibroplasia. Improved visual outcome with early vitamin E. Ophthalmology. 1983;90(5):428–35. pmid:6348635
- 75. Finer NN, Peters KL, Schindler RF, Grant GD. Vitamin E. Retrolental fibroplasia (RLF) and bronchopulmonary dysplasia (bpd): controlled trial in the low birth weight neonate. Pediatr Res. 1981;15:660.
- 76. Fish WH, Cohen M, Franzek D, Williams JM, Lemons JA. Effect of intramuscular vitamin E on mortality and intracranial hemorrhage in neonates of 1000 grams or less. Pediatrics. 1990;85(4):578–84. pmid:2179850
- 77. Hittner HM, Godio LB, Rudolph AJ, Adams JM, Garcia-Prats JA, Friedman Z, et al. Retrolental fibroplasia: efficacy of vitamin E in a double-blind clinical study of preterm infants. N Engl J Med. 1981;305(23):1365–71. pmid:7029275
- 78. Hittner HM. Retrolental fibroplasia and vitamin E. Ophthalmology. 1982;89(8):987–8.
- 79. Johnson L, Quinn GE, Abbasi S, Otis C, Goldstein D, Sacks L, et al. Effect of sustained pharmacologic vitamin E levels on incidence and severity of retinopathy of prematurity: a controlled clinical trial. J Pediatr. 1989;114(5):827–38. pmid:2654350
- 80. Johnson L, Bowen FW Jr, Abbasi S, Herrmann N, Weston M, Sacks L, et al. Relationship of Prolonged Pharmacologic Serum Levels of Vitamin E to Incidence of Sepsis and Necrotizing Enterocolitis in Infants with Birth Weight 1,500 Grams or Less. Pediatrics. 1985;75(4):619–38.
- 81. Pathak A, Roth P, Piscitelli J, Johnson L. Effects of vitamin E supplementation during erythropoietin treatment of the anaemia of prematurity. Arch Dis Child Fetal Neonatal Ed. 2003;88(4):F324–8. pmid:12819167
- 82. Romero-Maldonado S, Montoya-Estrada A, Reyes-Muñoz E, Guzmán-Grenfell AM, Torres-Ramos YD, Sánchez-Mendez MD, et al. Efficacy of water-based vitamin E solution versus placebo in the prevention of retinopathy of prematurity in very low birth weight infants. Medicine. 2021;100(31):e26765.
- 83. NCT03274596. Effect of vitamin E for prevention of retinopathy of prematurity: a randomized clinical trial. 2017. Available from: https://clinicaltrials.gov/study/NCT03274596
- 84. Sinha S, Davies J, Toner N, Bogle S, Chiswick M. Vitamin E supplementation reduces frequency of periventricular haemorrhage in very preterm babies. Lancet. 1987;1(8531):466–71. pmid:2881038
- 85. Speer ME, Blifeld C, Rudolph AJ, Chadda P, Holbein ME, Hittner HM. Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: evidence for efficacy of early intramuscular vitamin E administration. Pediatrics. 1984;74(6):1107–12. pmid:6504632
- 86. Chiswick M, Gladman G, Sinha S, Toner N, Davies J. Vitamin E supplementation and periventricular hemorrhage in the newborn. Am J Clin Nutr. 1991;53(1 Suppl):370S–2S. pmid:1985413
- 87. Tripathi S, Mishra TK, Mathur NB. Vitamin E supplementation in exclusively breastfed VLBW infants. Indian Pediatr. 2011;48(11):889–91. pmid:21719935
- 88. Watts JL, Milner R, Zipursky A, Paes B, Ling E, Gill G, et al. Failure of supplementation with vitamin E to prevent bronchopulmonary dysplasia in infants less than 1,500 g birth weight. Eur Respir J. 1991;4(2):188–90. pmid:2044736
- 89. Watts JL, Paes BA, Milner RA, Zipursky A, Gill GJ, Fletcher BP. Randomized controlled trial of vit. e. and bronchopulmonary dysplasia (BPD). Pediatr Res. 1981;15:686–686.
- 90. Hunnali CR, Devi U, Kitchanan S, Sethuraman G. Three Different Regimens for Vitamin K Birth Prophylaxis in Infants Born Preterm: A Randomized Clinical Trial. J Pediatr. 2023;255:98–104. pmid:36343740
- 91. CTRI/2022/02/040396. A randomised controlled trial comparing vitamin K status in less than 32 weeks and or less than 1500 gms after 3 prophylactic dosage regimens (0.3 vs 0.5 mg vs 1mg IM) at birth. 2022. Available from: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NjYwODM=&Enc=&userName=CTRI/2022/02/040396
- 92. Sethi A, Sankar MJ, Thukral A, Saxena R, Chaurasia S, Agarwal R. Prophylactic Vitamin K Administration in Neonates on Prolonged Antibiotic Therapy: A Randomized Controlled Trial. Indian Pediatr. 2019;56(6):463–7. pmid:31278224
- 93. Bass WT, Malati N, Castle MC, White LE. Evidence for the safety of ascorbic acid administration to the premature infant. Am J Perinatol. 1998;15(2):133–40. pmid:9514139
- 94. Darlow BA, Buss H, McGill F, Fletcher L, Graham P, Winterbourn CC. Vitamin C supplementation in very preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2005;90(2):F117–22. pmid:15724034
- 95. Doyle J, Vreman HJ, Stevenson DK, Brown EJ, Schmidt B, Paes B, et al. Does vitamin C cause hemolysis in premature newborn infants? Results of a multicenter double-blind, randomized, controlled trial. J Pediatr. 1997;130(1):103–9. pmid:9003858
- 96. Haiden N, Klebermass K, Cardona F, Schwindt J, Berger A, Kohlhauser-Vollmuth C, et al. A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity. Pediatrics. 2006;118(1):180–8. pmid:16818564
- 97. Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Arch Dis Child Fetal Neonatal Ed. 2005;90(2):F103-8. pmid:15724031
- 98. Shenai JP. Vitamin A supplementation in very low birth weight neonates: rationale and evidence. Pediatrics. 1999;104(6):1369–74. pmid:10585990
- 99. Brown CC, Noelle RJ. Seeing through the dark: New insights into the immune regulatory functions of vitamin A. Eur J Immunol. 2015;45(5):1287–95. pmid:25808452
- 100. Rakshasbhuvankar AA, Simmer K, Patole SK, Stoecklin B, Nathan EA, Clarke MW, et al. Enteral Vitamin A for Reducing Severity of Bronchopulmonary Dysplasia: A Randomized Trial. Pediatrics. 2021;147(1):e2020009985. pmid:33386338
- 101. Faienza MF, D’Amato E, Natale MP, Grano M, Chiarito M, Brunetti G, et al. Metabolic Bone Disease of Prematurity: Diagnosis and Management. Front Pediatr. 2019;7:143. pmid:31032241
- 102. Dhandai R, Jajoo M, Singh A, Mandal A, Jain R. Association of vitamin D deficiency with an increased risk of late-onset neonatal sepsis. Paediatr Int Child Health. 2018;38(3):193–7. pmid:30003852
- 103. Cetinkaya M, Cekmez F, Buyukkale G, Erener-Ercan T, Demir F, Tunc T, et al. Lower vitamin D levels are associated with increased risk of early-onset neonatal sepsis in term infants. J Perinatol. 2015;35(1):39–45. pmid:25102323
- 104. Mailhot G, White JH. Vitamin D and Immunity in Infants and Children. Nutrients. 2020;12(5):1233. pmid:32349265
- 105.
Ribeiro KD d S, Fernandes Assunção DG, Maia Amorim NC, de Oliveira PG. Vitamin E nutrition in pregnancy and the newborn infant. Sixth Edition. Elsevier Inc; 2022. p. 295–302.e3.
- 106. Brion LP, Bell EF, Raghuveer TS, Soghier L. What is the appropriate intravenous dose of vitamin E for very-low-birth-weight infants?. J Perinatol. 2004;24(4):205–7. pmid:15067295
- 107. Clarke P, Mitchell SJ, Shearer MJ. Total and Differential Phylloquinone (Vitamin K1) Intakes of Preterm Infants from All Sources during the Neonatal Period. Nutrients. 2015;7(10):8308–20. pmid:26426042
- 108. Van Winckel M, De Bruyne R, Van De Velde S, Van Biervliet S. Vitamin K, an update for the paediatrician. Eur J Pediatr. 2009;168(2):127–34. pmid:18982351
- 109. Ozdemir H, Bilgen H, Alp Unkar Z, Kiykim E, Memisoglu A, Ozek E. Severe lactic acidosis in an extremely low birth weight infant due to thiamine deficiency. J Pediatr Endocrinol Metab. 2018;31(6):693–5. pmid:29715193
- 110. Oguz SS, Ergenekon E, Tümer L, Koç E, Turan O, Onal E, et al. A rare case of severe lactic acidosis in a preterm infant: lack of thiamine during total parenteral nutrition. J Pediatr Endocrinol Metab. 2011;24(9–10):843–5. pmid:22145490
- 111. Salvatori G, Mondì V, Piersigilli F, Capolupo I, Pannone V, Vici CD, et al. Thiamine Deficiency in a Developed Country: Acute Lactic Acidosis in Two Neonates Due to Unsupplemented Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2016;40(6):886–9. pmid:25591974
- 112. Körner RW, Müller C, Roth B, Vierzig A. Thiamin status of premature infants assessed by measurement of thiamin diphosphate in whole blood. Br J Nutr. 2013;109(12):2182–9. pmid:23020849
- 113. Cormack BE, Jiang Y, Harding JE, Crowther CA, Bloomfield FH, ProVIDe Trial Group. Neonatal Refeeding Syndrome and Clinical Outcome in Extremely Low-Birth-Weight Babies: Secondary Cohort Analysis From the ProVIDe Trial. JPEN J Parenter Enteral Nutr. 2021;45(1):65–78. pmid:32458478
- 114. Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic review of cases. Nutr Clin Pract. 2012;27(1):34–40. pmid:22307490
- 115. Raiten DJ, Reynolds RD, Andon MB, Robbins ST, Fletcher AB. Vitamin B-6 metabolism in premature infants. Am J Clin Nutr. 1991;53(1):78–83. pmid:1898584
- 116. Tokuriki S, Hayashi H, Okuno T, Yoshioka K, Okazaki S, Kawakita A, et al. Biotin and carnitine profiles in preterm infants in Japan. Pediatr Int. 2013;55(3):342–5. pmid:23316835
- 117. Friel JK, Andrews WL, Long DR, Herzberg G, Levy R. Thiamine, riboflavin, folate, and vitamin B12 status of infants with low birth Weights receiving enteral nutrition. J Pediatr Gastroenterol Nutr. 1996;22(3):289–95. pmid:8708883
- 118. Levy R, Herzberg GR, Andrews WL, Sutradhar B, Friel JK. Thiamine, riboflavin, folate, and vitamin B12 status of low birth weight infants receiving parenteral and enteral nutrition. JPEN J Parenter Enteral Nutr. 1992;16(3):241–7. pmid:1501354