Micronutrient Intakes and Health Outcomes in Preterm Infants

Abstract

Deficiency or excess of specific micronutrients is common in preterm infants and can have many effects on health outcomes, ranging from life-threatening electrolyte disturbances to long-term effects on growth, brain development, bone health, and the risk of retinopathy of prematurity (ROP). Iron supplementation of low birth weight infants reduces the risk of be-havioral problems. However, due to the risk of adverse effects, iron supplementation of very preterm infants in the NICU should be individualized, considering birth weight, postnatal age, diet, and serum ferritin concentrations. Sodium intakes should be minimized during the first 3 days of life in very preterm infants to avoid hypernatremia. However, after 4 days of age, sodium supplements can reduce hyponatremia and improve growth. Adequate paren-teral and enteral calcium and phosphorus intakes are crucial for the prevention of osteope-nia of prematurity. Screening of serum phosphate concentrations is useful. Deficiencies of docosahexaenoic acid (DHA) and arachidonic acid (AA) are frequently observed in extreme-ly preterm infants. A recent Swedish study suggests that combined DHA and AA supplemen-tation may reduce the risk of severe ROP. When prescribing enteral and parenteral nutrition for preterm infants, it is important to consider micronutrients. Many preterm infants will need different micronutrient supplements. 

. Micronutrients can be defined as all nutrients except the macronutrients (protein, fat, and carbohydrates). This definition includes all minerals, vitamins, and trace elements, for which recommended daily intakes in preterm infants are typically given in mg or pg rather than grams per kg. Essential fatty acids such as long-chain polyunsaturated fatty acids are often also included in the definition of micronutrients. Micronutrients do not contribute to any significant extent to the energy intake but are essential for a vast array of specific functions in the body.
Deficient or excessive intakes of micronutrients are common in preterm infants [1]. Deficiency or excess of a specific micronutrient can have a drastic health impact in preterm infants, such as a massive intracranial hemorrhage caused by vitamin K deficiency, life-threatening arrythmias caused by hyperkalemia or a femoral fracture due to calcium and phosphate deficiency. However, in most cases, micronutrients have more subtle, but still extremely important health effects on, e.g., growth, brain development, bone health, and the risk of retinopathy of prematurity (ROP), see Figure 1.


We have used iron as a model nutrient in our studies of the effects of early micronutrient intakes on long-term health. Iron is essential for heme synthesis, oxygen transport, and many enzyme functions. The capacity of iron to switch between its two oxidation states Fe2+ (ferrous) and Fe3+ (ferric) underlies its essential role in oxygen transport and electron transfer reactions. Preterm and low birth weight infants are at high risk of iron deficiency due to low iron stores at birth, high iron requirements due to rapid growth and iron losses due to frequent blood samplings during neonatal intensive care. Iron deficiency (ID) leads to anemia and may have adverse effects on brain development. Iron is essential for neurogenesis and the differentiation of brain cells during the third trimester, which is a sensitive period of brain growth and development. In animal models, a clear causal relationship has been demonstrated between ID in infancy and impaired brain development and function, an effect which may be irreversible. Several domains of brain function have been shown in animal models to be affected by ID, including myelination, neurotransmitter synthesis and function, energy metabolism, and neuronal growth and dendrite formation [2].

We randomized 285 otherwise healthy infants with marginally low birth weight (2,000-2,500 g) to receive 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks of age until 6 months of age [3]. About 50% of these infants were preterm, the rest term, small for gestational age. Iron supplementation significantly reduced iron deficiency and iron deficiency anemia at 6 months: in the placebo group, 36% of the infants had iron deficiency, and 10% had iron deficiency anemia, while the corresponding proportions were 4 and 0% in the 2 mg iron group [3]. At 3 years of age, the previously iron supplemented infants had significantly lower risk of behavioral problems, OR 0.24 (95% CI 0.07-0.84), and this effect remained at 7 years of age [4, 5]. Interestingly, the effect on behavioral problems at 7 years was mainly seen in externalizing behavior. This study together with other evidence is the basis of the current recommendation that all low birth weight infants should receive iron supplements during the first 6 months of life [6].

However, humans have no mechanism for iron excretion; iron is a highly reactive pro-oxidant and an essential nutrient for many pathogens. Thus, excessive iron supplements can have adverse effects, e.g. infections, diarrhea, poor growth, and even poor neurodevelopment [7]. It has recently been shown that iron supplements can cause dysbiosis of the gut microbiome, which may be a mechanism for some of these adverse effects. In a study of 72 healthy, iron-sufficient, non-anemic 6-month-old infants randomized to iron drops (6.6 mg/ day), high-iron formula (6.6 mg/day) or low-iron formula (1.3 mg/day) during 45 days, infants receiving iron drops had less lactobacillus and streptococcus and more clostridium and bacteroides species in the gut microbiome [8]. Preterm infants receiving multiple blood transfusions are also at risk of iron overload, and local practice regarding blood sampling, blood transfusions and erythropoietin treatment greatly influences iron requirements in very low birth weight in-fants [9]. For these reasons, it is important to individualize iron supplements for very preterm infants during the stay at the neonatal intensive care unit (NICU), considering birth weight, postnatal age, diet, and serum ferritin concentrations [7].

Zinc is a micronutrient which is essential for growth, immune defense, and wound healing. Unlike iron, there are no toxicity problems - the main concern with higher zinc intakes is an increased copper requirement due to competition at the intestinal absorption stage [10]. Traditional fetal accretion calculations have been based on preterm infants with weights between 1,500 and 2,000 g, but the theoretical requirements are higher for infants <1,500 g. A recent Cochrane meta-analysis concludes that zinc supplements for preterm infants may decrease mortality and probably improves weight gain and linear growth [11]. However, the included studies used quite different doses of zinc. In conclusion, zinc requirements in very low birth weight infants are probably higher than previously believed, likely about 2-3 mg/kg/day.

Sodium is the principal cation in extracellular fluid and its concentration influences intravascular and interstitial volumes and blood pressure. Sodium is important for growth but also plays roles in such diverse processes as bone mineralization, nerve conduction, and nitrogen retention. Preterm infants are at risk of both hypernatremia and hyponatremia during the NICU stay. A slight increase in plasma sodium during the first 3 days of life is normal in newborns and reflects the postnatal weight loss and fluid loss from the extracellular compartment. Hypernatremia can be more severe in extremely preterm infants and typically reaches a peak at 3 days of age [12]. It is therefore recommended to minimize sodium intakes during the first 3 days of life in very preterm infants. However, after 4 days of age, hyponatremia becomes more common and iron requirements are high (3-8 mmol/kg/day) during the rest of the NICU stay. The reason for this is immature sodium reabsorption in the renal tubuli leading to sodium losses in the urine. Sodium supplements are thus frequently needed after the first few days of life in very preterm infants and have been shown to improve growth [13].

Calcium, phosphorus, magnesium, and vitamin D are some micronutrients which are essential for bone growth and development. Osteopenia or metabolic bone disease of prematurity is usually caused by deficiencies in calcium and phosphorus, since these two minerals are especially difficult to deliver in sufficient quantities both in parenteral and enteral nutrition due to their tendency for precipitation. Osteopenia is associated with dolichocephalic head flattening of preterm infants, and severe osteopenia leads to fractures. Along with improved nutrition, the incidence of rickets in infants with birth weight <1,000 g has decreased from approximately 50% in the 1980s to about 15% [14]. However, severe cases with fractures are still occasionally seen today in NICUs, and infants on long-term parenteral nutrition are at especially high risk. In order to prevent osteopenia, it is important to provide adequate amounts of calcium,phosphorus, and vitamin D to all preterm infants. In addition, screening tests are recommended in order to optimize calcium and phosphorus intakes and to discover early signs of osteopenia [15]. Screening may involve serum measurements of phosphate, alkaline phosphatase, and parathyroid hormone, or concentrations of calcium and phosphate in urine. Even though a low serum phosphate concentration is a hallmark of osteopenia after the first few weeks of life in preterm infants, it is important to note that osteopenic infants usually have normal or high serum calcium concentrations.

In addition to the late hypophosphatemia of osteopenia, early hypophosphatemia is commonly observed in very low birth weight infants during the first week of life. Some of these infants have severe hypophosphatemia (<1.0 mmol/L), which can lead to life-threatening cardiac arrythmias and may increase the risk of sepsis [16]. The mechanism behind early hypophosphatemia is not phosphorus deficiency but rather a temporary shift of electrolytes between body fluid compartments, similar to refeeding syndrome [17]. Amino acids from parenteral nutrition are transported into cells together with phosphorus and potassium, depleting the extracellular compartment of these two cations. The resulting hypophosphatemia causes phosphorus to be released from bone tissue, leading to an increase in serum calcium. Thus, this condition is characterized not only by hypophosphatemia but also hypokalemia and hypercalcemia.

Linoleic acid and alpha linolenic acid are the essential fatty acids in the omega 6 and omega 3 series, respectively. These are converted in the liver by the delta 6 desaturase to form arachidonic acid (AA) and eicosapentaenoic acid, which in turn is converted to docosahexaenoic acid (DHA). Even though late or moderately preterm infants have similar delta 6 desaturase activity as term infants [18], very preterm infants are believed to have an immature delta 6 desaturase activity, and DHA and AA, and very low levels of serum DHA and AA have been observed from 7 days of age in extremely preterm infants, even when they receive modern parenteral nutrition solutions, which provide insufficient amounts of DHA and AA [19]. Since long-chain polyunsaturated fatty acids are essential for normal brain and eye development, it is important to ensure an ad-equate intake of DHA and AA in the diet of very preterm infants. Notably, these fatty acids are present in breast milk, but the concentrations are highly dependent on the maternal diet, which are commonly lacking in fish and seafood. In an Australian study, 1,273 preterm infants born before 29 gestational weeks were randomized to DHA (60 mg/kg/day) or placebo [20]. Since low DHA levels have been associated with BPD, the primary outcome in this study was BPD. Unexpectedly, the study instead showed an increased risk of BPD (aOR 1.13, 95% CI 1.02-1.25) as well as increased risk of BPD or death (aOR 1.11, 95% CI 1.001.23) in the DHA group. Notably, the intervention did not include AA.

In a recent Swedish study, 101 extremely preterm infants born <28 weeks of gestation were randomized to receive supplements with DHA (50 mg/kg/day) and AA (100 mg/kg/day) or placebo from <3 days until term age, the primary outcome being severe ROP [21]. Interestingly, the incidence of severe ROP was significantly reduced with a risk ratio of 0.50 (95% CI 0.28-0.91, p = 0.02). This suggests that extremely preterm infants may benefit from combined DHA and AA supplementation. The safety and efficacy of this intervention is currently being evaluated in a Norwegian randomized, controlled trial involving 120 preterm infants born before 29 weeks of gestation [22]. The primary outcome of that trial is brain maturation as assessed by magnetic resonance imaging at term age, which hopefully also will give more insight on the effects of DHA and AA supplements on brain development in preterm infants.

Even though the examples given above only cover a few micronutrients, they highlight the importance of micronutrients for short- and long-term health out-comes in preterm infants. When prescribing enteral and parenteral nutrition for preterm infants, it is important to consider not only macronutrients but also the micronutrients. Parenteral nutrition solutions need to have an appropriate mi-cronutrient balance to cover requirements without causing excessive intakes of some micronutrients, which may have adverse effects. Likewise, human milk fortifiers and preterm formulas need to have an appropriate micronutrient composition. Especially challenging clinical situations are preterm infants who are on a combination of enteral and parenteral nutrition, and fully breast milk-fed infants who do not receive full-dose human milk fortifier. Many preterm infants will need additional micronutrient supplements, which may involve several sep-arate supplements of vitamins, different minerals, and trace elements (see Fig. 2).
Parenteral micronutrient requirements for preterm infants are published in the ESGPHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition from 2018 [23]. Enteral micronutrient requirements for preterm infants are included in the ESPGHAN recommendations from 2010 [24], but these guidelines are currently being updated, with estimated publication in late 2021 or early 2022. A difficulty when prescribing a combination of enteral and parenteral nutrition is that it is not possible to add the micronutrient intakes from these two sources (which is commonly done for macronutrients) since the intestinal absorption of different micronutrients ranges between 8 and 100% with many micronutrients having a bioavailability of around 50% or lower [1]. Modern software tools allow calculation of micronutrient intakes also for preterm infants who receive a combination of enteral and parenteral nutrition as well as different supplements and fortifiers, which facilitates correct prescriptions and improves micronutrient intakes [25].



Our knowledge on micronutrient requirements in preterm infants is still far from complete, even though several of the micronutrients are targets of active research. Results of future research will give even better data upon which to base recommendations for improved short- and long-term health in preterm infants.

Conflict of Interest Statement

Magnus Domellof has received honoraria or consultation/speaker fees from Abbvie AB, Arla Foods Ingredients, Baxter AB, Biostime Institute of Nutrition and Care, Chiesi Pharma AB, Danone Nutricia, Fresenius Kabi Sweden, Mead Johnson, Nestec Ltd. (Nestlé), Prolacta Bioscience and Semper AB, as well as grants/research supports from Baxter AB and Prolacta Bioscience.

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