Selenium is an essential trace element and a component of various proteins such as selenium-dependent glutathione peroxidase, selenoprotein P, and iodothyronine-5’-deiodinase [1]. Selenium is a cofactor required to maintain the activity of glutathione peroxidase and plays an important role in anti-oxidative processes in the human body [2]. Selenoprotein P is an important factor in the regulation of reactive oxygen species and has influence on both inflammation and immunity [3]. Further, iodothyronine-5’-deiodinase converts thyroxine (T4) to triiodothyronine (T3), involving selenium is the process of thyroid function [4].

When selenium is deficient in the human body, symptoms such as macrocytosis and pseudoalbinism can appear; severe cases can experience cardiomyopathy, muscle fatigue, and Keshan disease [5-8]. While cases of selenium excess are rare, its symptoms include nausea, diarrhea, hair loss, garlic-odor breath, and skin rash [9].

Selenium deficiency in infants most commonly occurs in preterm infants [10,11], in whom the storage capacity of selenium in the liver is limited compared to that of term infants. In addition, selenium is depleted quickly with rapid growth [12]. These factors can lead to low selenium level in the blood [13]. In addition, feeding intolerance is common in preterm infants due to limited gastric capacity, reduced gut mobility, and other factors. Therefore, there is a strong possibility of preterm infants with feeding intolerances becoming dependent on parenteral nutrition (PN) [1,14]. Selenium deficiency occurs more frequently with long-term PN that does not include selenium [15,16].

This review outlines the clinical issues associated with selenium deficiency and the guidelines on optimal selenium supplementation in infants.

Selenium level can be measured in whole blood, serum, plasma, urine, or hair. Alternatively, the activity of glutathione peroxidase in plasma or red blood cells can be used to measure selenium status. However, the activity of glutathione peroxidase is not a useful tool in preterm infants, as they are immature and might be influenced by exposure to supplemental oxygen [17].

Blood selenium level varies depending on the selenium concentration of the soil in each region, as well as personal eating habits. Some studies have reported plasma selenium concentrations of 50–150 mcg/L as the normal range in healthy infants and children, while others have reported 57–94 mcg/L as the normal range in infants at term [9,18]. One Korean study reported an average 57.6 mcg/L serum selenium level in infants 0–5 months old [19].

Serum selenium level is associated with age and increases with increasing age [20]. Preterm infants tend to show lower serum selenium level compared to term infants [21].

Selenium deficiency is often mentioned in association with a disease called Keshan disease and is the major cause of the disease. Patients with Keshan disease manifest congestive heart failure, acute heart failure, and cardiac arrhythmias, which can be life-threatening [8]. When Keshan disease first was identified in northeast China in the 1940s, the fatality rate was up to 80% [7].

Selenium deficiency is rare in healthy, well-fed infants but more common in patients receiving long-term PN [15]. Some cases with long-term PN have involved erythrocyte macrocytosis, loss of pigmentation of the hair and skin, and muscle weakness [5]. Low selenium concentration does not produce detectable clinical manifestation in all patients, complicating its diagnosis. However, it is important to prevent selenium deficiency because of its possibility to result in fatal symptoms [8].

Preterm infants

Fetal selenium storage begins at the third trimester of pregnancy, and preterm infants have less selenium stored in the liver compared to term infants [12]. Selenium level in umbilical cord blood has been correlated with gestational age and maternal selenium level. One study showed lower selenium level in the umbilical cord blood of preterm infants than that of term infants [22]. Similarly, many other studies have reported lower blood selenium level in preterm infants than term infants [10,11,23]. Another study showed more frequent selenium deficiency in extremely low birth weight infants and very low birth weight infants compared to normal birth weight infants [24].

Long-term PN

The risk of selenium deficiency increases with long-term PN, as selenium is often not included in nutritional supplementation or included in insufficient amount. One study reported a significant decline in blood selenium level in low birth weight infants administered PN for one week [25]. Another study showed that preterm infants supplied with 88% of their total daily energy requirements through PN showed remarkable decrease in plasma serum selenium concentration [26]. Cases of growth retardation and pseudo-albinism accompanied by hair loss due to selenium deficiency have been reported in infants receiving long-term PN [27]. When selenium is mixed with a high concentration of ascorbic acid, a reduction reaction may result in precipitation of selenium, hindering selenium supplementation in short-term PN in certain cases [28]. As a result, selenium deficiency is more common in patients who receive selenium-free PN.

Many studies are ongoing to discover the relationships between selenium deficiency and bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), sepsis, and hypothyroidism, in which selenium plays an important role (Table 1).

Table 1

Literature evaluation of selenium and relevant clinical outcomes

Relevant clinical outcome	Study design	Patients (or participants)	Selenium supplementation	Results	Reference
BPD	Prospective observational	79 infants with VLBW or GA ≤32	-	Duration of oxygen dependence increased by 58% when the plasma selenium level was lowered by 0.1 μM/L	Darlow et al. [29]
	Prospectiveobservational	38 preterm infants with GA ≤32	-	Serum selenium concentration was lower at 1 month after birth in patients with BPD (38.5±14.1 vs. 45.4±18.7 mcg/L, P=0.02)	Mostafa-Gharehbaghi et al. [30]
	Prospective observational	54 preterm infants with GA ≤30	-	No significant difference in selenium level between infants with and without BPD at 1 month after birth (P=0.40)	Peirovifar et al. [31]
ROP	Prospective	Observation group: 30 preterm infants who had high risk of ROP Control: 18 normal infants	-	Preterm infants with ROP showed much lower level of serum selenium than normal infants at term (121.74±97.54 vs. 202.92±44.71 mcg/L, P<0.01)	Yang et al. [33]
	RCT	534 VLBW infants	7 mcg/kg/day (PN) or 5 mcg/kg/day (oral)	No significant difference [relative risk 0.91 (0.69–1.21)]	Darlow et al. [34]
	RCT	38 preterm infants	3 mcg/kg/day (PN)	No significant difference	Daniels et al. [35]
Sepsis	RCT	534 VLBW infants	7 mcg/kg/day (PN) or 5 mcg/kg/day (oral)	Fewer infants in the selenium group experienced nosocomial sepsis after the first week of life (25.1% vs. 33.3%, P=0.038)	Darlow et al. [34]
	RCT	38 preterm infants	3 mcg/kg/day (PN)	Incidence of sepsis, defined as microbiologically confirmed or requiring antibiotics for at least 5 days, was greater in the PN without selenium group (79%, n=15 vs. 42%, n=8, P≤0.05)	Daniels et al. [35]
	RCT	90 VLBW infants	10 mcg/day (oral)	The total incidence of any LOS (i.e., culture-proven as well as probable sepsis) was significantly reduced by selenium supplementation [7/45 (15.55%) in selenium vs. 22/45 (48.88%) in placebo, P=0.001]	Aggarwal et al. [36]
Hypothyroidism	Prospective	29 ELBW infants	2 mcg/kg/day (PN)	No significant correlation between serum selenium level and hypothyroidism	Klinger et al. [10]

BPD = bronchopulmonary dysplasia; ROP = retinopathy of prematurity; RCT = randomized clinical trial; VLBW = very low birth weight; GA = gestational age; ELBW = extremely low birth weight; PN = parenteral nutrition; LOS = late-onset sepsis.

BPD

BPD is a chronic lung disease that commonly occurs in preterm infants treated with oxygen for illnesses related to oxidative stress. One study reported lower plasma selenium concentration in preterm infants with BPD and an increase in duration of oxygen dependence by 58% when the plasma selenium level was lowered by 0.1 μM/L [29]. Another study reported that their BPD group had lower blood selenium level than the non-BPD group at 1 month after birth [30]. In addition, a prior study reported no significant differences in selenium level between infants with and without BPD at 1 month after birth; however, the selenium level in infants with BPD was lower than that of their first umbilical cord blood samples [31]. All of the studies mentioned above focused on the association of BPD and blood selenium level. Therefore, additional research is necessary to discover the cause-and-effect relationship between selenium deficiency and BPD.

ROP

ROP occurs when abnormal blood vessels grow in the retina and is more likely to occur in infants of younger gestational ages. One study reported that the concentration of selenium-dependent glutathione peroxidase was relatively higher in the retinas of preterm infants [32]. Similarly, one study reported that preterm infants with ROP showed much lower selenium serum level than normal term infants [33]. However, several other studies did not find any significant differences between groups with and without selenium supplementation [34,35]. More research is necessary to determine the relationship between ROP and selenium.

Sepsis

Previous studies were conducted under the assumption that sepsis is related to the antioxidant action and immune-related functions of selenium. One study reported that a group of infants given selenium supplementation had a lower incidence of sepsis at one week after birth compared to a placebo group [34]. Another study reported that a group of infants given intravenous selenium at 3 mcg/kg/day had much lower incidence of microbiologically confirmed cases of sepsis or sepsis requiring treatment with antibiotics for 5 days or more compared to the group who did not receive selenium [35]. Furthermore, a prior study reported that a group of preterm infants with very low birth weight who received daily oral supplementation of 10 mcg of selenium had lower incidence of sepsis confirmed by blood culture tests compared to a placebo group [36].

Hypothyroidism

Selenium is known to be associated with thyroid function and is a component of iodothyronine deiodinase type 1, which converts T4 to T3. Selenium deficiency reduces the activity of selenoprotein glutathione peroxidase, which detoxifies hydrogen peroxide and prevents lipid peroxidation [37]. Oral supplementation of 50 mcg of selenium for 2 months in 52 healthy children led to significant reductions of the concentrations of T4, free T4, and reverse T3 in the serum [38]. However, one study on extremely low birth weight infants showed that more than half of infants with low serum selenium had normal free T4 concentration and observed no correlation between serum selenium level and hypothyroidism [10].

Guidelines on the adequate amount of selenium supplementation in infants through PN varies (Table 2). The American Society for Parenteral and Enteral Nutrition (ASPEN) recommends 1.5–2 mcg/kg/day of selenium for preterm neonates <3 kg and 2 mcg/kg/day of selenium for term neonates through PN [39]. Further, ASPEN suggested supplementing 1.5–4.5 mcg/kg/day for preterm infants [40]. The European Society for Clinical Nutrition and Metabolism (ESPEN)’s 2005 guideline recommended 2–3 mcg/kg/day of selenium supplementation for PN-dependent low birth weight infants [41]. However, this guideline was revised in 2018 and now recommends 2–3 mcg/kg/day of selenium supplementation for term infants, while the amount for preterm infants was increased to 7 mcg/kg/day [42]. The results of several studies led to this increase in recommended amount of selenium supplementation.

Table 2

Parenteral selenium daily recommendation (mcg/kg/day)

Guideline	ASPEN (2005) (Corkins et al. [39])	ASPEN position paper (2012) (Vanek et al. [40])	ESPEN (2005) [41]	ESPEN (2018) (Domellöf et al. [42])
Preterm infants	1.5–2	1.5–4.5	2–3 (parenterally fed LBW infants)	7
Term infants	2	2	-	2–3

ASPEN = American Society for Parenteral and Enteral Nutrition; ESPEN = European Society for Clinical Nutrition and Metabolism; LBW = low birth weight.

Previous studies have concluded that 2–3 mcg/kg/day of selenium supplementation is insufficient for newborns, especially for preterm newborns (Table 3). One study showed that supplementation of 3 mcg/kg/day of selenium for preterm infants through PN prevented selenium deficiency; however, it was insufficient to reach the level attained in breastfed term infants [35]. In another study, 29 extremely low birth weight infants were given 2 mcg/kg/day of selenium through PN, 26 of whom had serum selenium level lower than 57 mcg/L, which was defined as normal [10]. One United States study showed that almost all infants were selenium deficient when receiving 2 mcg/kg/day of selenium, and the proportion of infants with deficiencies was reduced when 6 mcg/kg/day or more of selenium was administered [43]. ESPEN cited a randomized clinical trial on 534 very low birth weight infants when it increased the recommended dose for selenium supplementation. That study showed meaningful increase in plasma selenium level compared to healthy term infants when 7 mcg/kg/day of selenium was supplemented [34]. That study was conducted in New Zealand, where the selenium level in soil is low, which leads to relatively low selenium levels in breast milk. All of these studies imply that the previously recommended selenium supplementation of 2–3 mcg/kg/day only prevents reduction of selenium level. Higher doses of selenium supplementation are necessary to improve blood selenium level.

Table 3

Literature evaluation of parenteral selenium supplementation

Study design	Patients (or participants)	Selenium supplementation	Results	Reference
RCT	38 preterm infants	3 mcg/kg/day	Selenium supplementation prevented depletion	Daniels et al. [35]
Prospective	29 ELBW infants	2 mcg/kg/day	Twenty-six infants had serum selenium level lower than the normal 57 mcg/L	Klinger et al. [10]
Retrospective	49 PN-dependent infants aged ≤1 year	Shortage period: 2.1±1.2 mcg/kg/day Nonshortage period: 3.8±1 mcg/kg/day	A linear relationship was observed between intravenous selenium dose and selenium level. At doses ≤2 mcg/kg/day, nearly 100% of infants were deficient (P<0.01); when doses ≥6 mcg/kg/day were provided, the incidence of selenium deficiency decreased	Chen et al. [43]
RCT	534 VLBW infants	7 mcg/kg/day (PN) or 5 mcg/kg/day (oral)	Mean plasma seleniume concentration at 28 days increased in the supplemented group (0.56 mcmol/L) but decreased in the control group (0.29 mcmol/L) (P<0.0001)	Darlow et al. [34]

RCT = randomized clinical trial; ELBW = extremely low birth weight; PN = parenteral nutrition; VLBW = very low birth weight.

Regional variability is seen with selenium consumption based on dietary intake. Selenium supplementation in infants fed with breast milk is estimated to be 2.5 mcg/kg/day with 80% bioavailability [41,44]. Selenium level in breast milk show regional variability and are reported to be associated with the selenium level in the soil of each region, as well as the mother’s selenium consumption [45]. Furthermore, an infant’s blood selenium level varies depending on whether it is fed with breast milk or infant formula. One study showed that term infants fed with breast milk had higher level of selenium than those fed with infant formula [13]. One German study reported that infants fed with breast milk maintained their plasma selenium level at birth until 4 months of age, while those fed with infant formula showed decrease in plasma selenium level [46]. In addition, that study reported that infants fed with hypoallergenic formula had lower selenium level compared to those fed with regular formula. The recommended supplementary dose of selenium varies among guidelines (Table 4). ASPEN recommends 1.3–4.5 mcg/kg/day of selenium to be supplemented through enteral nutrition for preterm infants [40,47]. The European Society for Paediatric Gastroenterology Hepatology and Nutrition 2010, in contrast, recommends 5–10 mcg/kg/day of selenium for preterm infants [48]. Recommendations for adequate selenium supplementation differ among regions and countries.

Table 4

Enteral selenium daily recommendation

Guideline	Preterm infants	Term infants
ASPEN position paper (2012) (Vanek et al. [40])	1.3–4.5 mcg/kg/day	15 mcg/day
ESPGHAN (2010) (Agostoni et al. [48])	5–10 mcg/kg/day	-

ASPEN = American Society for Parenteral and Enteral Nutrition; ESPGHAN = European Society for Paediatric Gastroenterology Hepatology and Nutrition.

Selenium deficiency may be associated with oxidative injuries and diseases such as BPD and sepsis. Preterm infants and those given long-term PN are not only at risk of low baseline selenium level, but also of selenium deficiency secondary to insufficient supplementation. Therefore, infants’ clinical statuses and levels of selenium deficiency need to be considered when supplementing with appropriate amounts of selenium, and regular follow-up monitoring should be conducted. Future studies should consider multiple risk factors in order to optimize selenium dosing regimens for infants.

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