Preterm infants are at high risk of micronutrient deficiencies due to maternal deficiencies, low body stores at birth, and low nutritional intakes, such that most preterm infants require vitamin supplementations soon after birth [1
]. With the exception of vitamin D, the intake of most micronutrients is met by fortified breast milk and preterm infant formula feeds at enteral feed volumes greater than 150 ml/kg/day. Whilst similar amounts of vitamins and minerals are generally provided by most commercial preterm nutritional products, individual requirements may vary significantly depending on gestational ages, stores at birth, and clinical factors.
Several international consensus recommendations exist for daily micronutrient intakes for fully enterally fed, stable-growing preterm infants with birth weights up to 1500 g (very low birth weights; VLBWs, Table 1
). The most recent of these, Koletzko et al. 2014, is based on current knowledge and expert group discussions [1
]. Similar published recommendations on nutrient intakes are not available for low birth weight (LBW; <1.5–<2.5 kg) babies.
Estimates of requirements for calcium and phosphorus in preterm infants are based on studies of intrauterine mineral accretion rates and calcium absorption and retention. Most studies in preterm infants have based vitamin D sufficiencies on the Institute of Medicine’s definition of a 25-hydroxyvitamin D level (>50 nmol/L), which is based on biomarkers from adult studies; however, no definition of vitamin D deficiencies based on biological functions is available for preterm infants [4
]. In addition to having a negative impact on bone health, low neonatal vitamin D levels have been associated with greater risks of respiratory distress syndrome [5
], bronchopulmonary dysplasia (BPD) [6
], and sepsis [7
Iron deficiencies during infancy in healthy term infants are associated with irreversible, long-term neurodevelopmental impairments [8
]. Early iron supplementations in VLBW infants have been shown to be safe and reduce the risk of iron deficiencies [10
]; however, it is unclear whether iron supplementations in preterm infants have long-term benefits for growth and neurodevelopmental outcomes.
The evidence base is limited for quantifying ideal intakes of other micronutrients and long-term outcomes. Fat-soluble vitamins A and E act as antioxidants, and pharmacological doses may confer benefits for high-risk infants in the prevention of BPD, retinopathy of prematurity (ROP), and necrotising enterocolitis (NEC) [12
]. A lack of data exists on the potential toxicity and long-term effects of high doses of fat-soluble vitamins.
The lack of evidence for optimal doses and long-term safety has resulted in significant practice variations across neonatal units, and subsequently, micronutrient intakes above or below recommended ranges. In addition, the continuation of historical practices and a lack of clinician knowledge about the nutritional compositions of preterm nutritional products may result in unnecessary supplementations. The aim of this survey was to investigate current vitamin and mineral supplementations practices in Australian and New Zealand (NZ) neonatal intensive care units (NICUs) and special care nurseries (SCNs) and compare these with consensus recommendations and published evidence on dosages and outcomes of supplementations in preterm infants.
2. Materials and Methods
As part of a wider study of neonatal nutrition practices and dietitian resourcing, a link to a two-part electronic pretested survey (Survey Monkey, SVMK Inc., San Mateo, CA, USA) consisting of multiple-choice questions was emailed on 16 July, 2018 to 50 Australasian Neonatal Dietitians Network (ANDiN) members working in a NICU or SCN in Australia or New Zealand. Non-ANDiN member neonatal dietitians practising in Australia or New Zealand were also invited to participate. Non-responders were sent a reminder email after four weeks and again just prior to the survey closing. If no response was received from a level 3 NICU site listed in the Australian and New Zealand Neonatal Network (ANZNN) directory, an email was sent to a neonatologist at the site to provide contact details for the neonatal dietitian or confirm that they did not have a dietitian. The survey closed on 10 October, 2018. Responses were stored on a password-protected online site.
Survey questions for Part 2 of the survey can be found in Supplementary Materials
. The Checklist for Reporting Results of Internet E-Surveys (CHERRIES) statement guidelines were followed for reporting survey results. Descriptive statistics were used to examine the distribution of survey responses. Percentages were calculated for categorical variables.
Our survey showed that the majority of preterm infants in Australian and New Zealand neonatal units were supplemented with around 400 IU/day of vitamin D, although there were wide variations in individual unit supplementation criteria. Supplementations with modest doses of vitamin D (maximum intake up to 400 IU/day) have previously been shown to achieve adequate bone mineralisation, and similar serum vitamin D concentrations in preterm infants when compared with higher doses of 800–1000 IU/day [13
]. In an Australian observational study of moderately preterm infants, total intakes of 600 IU/day resulted in lower proportions of vitamin D-deficient infants at 36 weeks PMA than at birth [16
]. In more recent randomized controlled trials, Natarajan et al. [17
] suggested that 800 IU/day reduced the incidences of vitamin D deficiencies at term CA but showed no improvements in bone mineralization at term and three months CA. Anderson-Berry et al. [18
] showed greater improvements in serum vitamin D concentrations and bone density measurements of infants born <32 weeks supplemented with 800 IU, compared to 400 IU/day.
Data are lacking on Vitamin D supplementations in extremely low birth weight (ELBW, <1000 g) infants. Fort et al. found that although greater prevention of vitamin D deficiencies in ELBW infants was achieved at day 14 by supplementations of 800 IU/day, higher than desired concentrations of serum vitamin D were seen at 28 days of age [19
]. The authors suggested that higher initial doses for shorter durations to restore vitamin D concentrations to normal, followed by lower dosages, may be an ideal regime for ELBW infants.
The majority of units supplemented iron in preterm infants in line with current recommendations for the first 12 months, although, in some units, iron intakes were double the recommendations at the time of discharge. A 2012 Cochrane review did not find any evidence that an iron dose greater than 3 mg/kg/day resulted in improved haematological outcomes, and such doses may cause potential oxidative damage due to poor regulation of iron absorptions in ELBW infants in the first month of life [10
The optimal dose, timing, and duration of iron supplementation is yet to be elucidated, and large-scale randomized trials are required. The exact dosages and timings of initiation may vary depending on birth weights and gestational ages, with extremely preterm or growth-restricted infants having higher requirements due to greater post-natal growth velocities. Most units commenced prophylactic enteral iron supplementations (either via human milk fortifiers containing iron or as ferrous sulphate) within the first month after birth, coinciding with the achievement of full, fortified enteral feeds. Early supplementations (within 2–3 weeks of age) have been associated with smaller drops in haemoglobin and ferritin and lowered frequencies of blood transfusions, compared with late supplementations (greater than four weeks) [20
]. A five-year follow-up study of VLBW infants randomized to early or late iron supplementations showed trends toward beneficial effects on long-term neurocognitive and psychomotor development with early supplementations [21
Haematological benefits of early supplementations have also been shown in LBW infants [22
], and follow-up studies have suggested long-term benefits of behavioral functions at seven years in LBW infants supplemented with 2 mg/kg/day iron from six weeks to six months of age [24
]. Currently, there are no recommended nutrient intakes for LBW infants, and our study observed that at least 20% of units did not supplement iron in infants with birth weights greater than 2000 g and/or born moderate-to-late preterm.
Most units did not routinely prescribe other additional vitamins or minerals, likely due to nutritional products meeting current nutritional recommendations and a lack of level 1 evidence for further supplementations in preterm infants. Four units (15%) prescribed enteral vitamin E, in addition to fortified feeds. A 2003 Cochrane database review did not support the routine use of high-dose vitamin E given intravenously due to increased late-onset sepsis [25
]. No large, randomized controlled trials on enteral vitamin E supplementations and clinical outcomes have been conducted.
Additional calcium and phosphate were routinely supplemented in four units (15%), and additional folic acid in three units (11%), in our survey. A survey of enteral nutrition practices in Australasian neonatal units conducted in 2008 showed that 13% of units routinely supplemented phosphate and 29% prescribed folic acid [26
]. This was despite there being sufficient folate in breast milk fortifiers and preterm formulas. We found no evidence in the literature suggesting supplementations of these additional micronutrients at levels higher than estimated requirements were beneficial.
The incidental supplementations of vitamin A in many units using vitamin D-containing multivitamins resulted in vitamin A intakes slightly above current recommended levels but well below levels considered to be toxic. A meta-analysis of relatively high-dose vitamin A supplementations in VLBW infants concluded that the incidence of oxygen requirements by 36 weeks PMA was reduced, and there was a trend towards reductions of ROP and sepsis [27
]. The absorption of vitamin A by the preterm gut is known to be poor; therefore, most studies have used intramuscular injections of vitamin A. However, the intramuscular route of administration is not widely accepted because of the discomfort associated with repeated injections. An RCT is currently underway to determine the effect of an enteral water-soluble vitamin A on BPD [28
One strength of this survey was the high response rate from dietitians working in NICUs; however, there were lower response rates from SCNs. A number of dietitians working in smaller units were not aware of unit guidelines or criteria for vitamin or mineral supplementations. Another limitation of this survey was that information on doses of supplements such as calcium, phosphate, folate, and vitamin E was not collected.