Zinc is one of the most abundant trace elements in humans [1]. Zinc is functional for the activity of a number of proteins (i.e., enzymes, membrane proteins, gene-regulatory proteins, and hormonal receptors) involved in most major metabolic pathways [2]. Zinc interacts with proteins in different ways: (i) by promoting enzymatic processes; (ii) by maintaining quaternary structure stability (Figure 1) [2]; or (iii) by favoring interactions with other molecules (i.e., proteins, nucleic acids) [3]. The six enzyme classes established by the International Union of Biochemistry Enzymes, i.e., oxidoreductases, transferases, hydrolases, lysases, isomerases and ligases, all require zinc [1]. During the enzymatic processes, zinc may have (1) a catalytic role (it has roles directly in catalytic processes), (2) a coactive role (by enhancing or diminishing catalytic functions) and a structural role (it is required for quaternary structure stability of enzymes) [4]. Metallothioneins (MTs) are the most abundant cysteine-rich proteins containing zinc [5]. These proteins have an important antioxidant activity and stabilize cell membranes only in the presence of zinc [6]. Zinc is also required for the DNA binding proteins involved in the regulation of gene expression [7,8,9]. The glucocorticoid and estrogen receptors are examples of zinc hormonal receptor proteins. They are members of a multigene family that includes receptors for thyroid hormone, retinoic acid, and vitamin D [10]. The DNA binding domain of these proteins contains zinc. Removal of this element yields hormonal receptors that do not bind DNA when activated by glucocorticoids or estrogens.

The characteristic of the zinc is, certainly, its even distribution throughout the body. Functionally, zinc participates in cell division and growth, intestinal electrolyte absorption, neurotransmission, immune response, thymus activity, and vision (Figure 2) [11,12,13,14,15,16,17]. Consequently, numerous functions in humans are affected by zinc deficiency, particularly during periods of increased metabolism. However, clinical manifestations become evident only with severe deficiency; dermatitis, diarrhea, neurological disorders, growth failure, infections and delayed tissue healing following injuries are the most frequent clinical consequences of zinc deficiency. In early life, zinc deficiency may affect embryogenesis and may influence duration of pregnancy. After birth, a major factor associated with the development of zinc deficiency is its inadequate intake. Additional exacerbating factors include high physiological requirements, excessive losses by pathological conditions, intestinal failure and treatment with some drugs [18]. With some degree of variability, as with many other nutrients, human do not have functional reserves or body stores of available zinc, except neonates born at term, who may be able to draw on the hepatic zinc accumulated during the entire gestational period [19]. These aspects are of particular importance for preterm neonates. In this population, high requirements for growth and environmental injuries, physiological intestinal insufficiency and frequent use of antibiotics, significantly increase the risk of zinc deficiency. In addition, preterm birth reduces the duration of pregnancy and thus the amount of hepatic stores available during periods of reduced zinc intake.

Consequently, preservation of a positive zinc balance in the mother during pregnancy and lactation, and in neonates, is of critical importance in early life for the possible consequences on health, growth and development.

Starting from these considerations, we carried out a narrative review, analyzing current literature, with the subsequent aims to:

Explore the role of zinc in early life including embryogenesis, fetal and neonatal life.

We performed a systematic search of articles on the role of zinc in embryogenesis, during fetal life and in babies born prematurely. We conducted an electronic search in MEDLINE using the following medical subject headings and terms: “zinc” associated with “embryogenesis”, “fetus”, “preterm neonate” or “preterm newborn”. In addition, we made a manual search of the reference lists of all eligible articles. We limited the search to clinical trials, case reports and reviews in human and animal model, in English language. We selected and analyzed 81 studies (Table 1) and report the results here in a narrative review.

Zinc deficiency has been well documented in hospitalized premature neonates [48]. The risk of zinc deficiency increases in preterm and small for gestational age (SGA) neonates or in case of intestinal failure [49]. The high risk of deficiency derives from a combination of three main factors: (i) low body stores due to reduced time for placental transfer of zinc; (ii) potentially marginal intake, and (iii) increased endogenous losses. Intestinal zinc absorption is not regulated by zinc status, rather, it is absorbed as a percentage of intake. However, in term babies, zinc absorption improves with decreasing serum zinc concentration and zinc stores are mobilized, enabling infants to avoid clinical deficiency. Zinc content in human milk varies considerably (0.7 to 1.6 mg/L) and declines with time [50,51,52,53,54]; while colostrum contains 8–12 mg/L, human milk at seven days of neonatal life contains 3–6 mg/L of zinc [50,51,52,53,54]. These values rapidly decrease at 1–3 mg/L at 1 month of life [50,51,52,53,54]. No clear differences in the zinc content of human milk were seen in women taking mineral supplements [50,51,52,53,54]. Preterm infant consuming 180 mL/kg per day of supplemented human milk would receive only 0.5–1 mg/kg per day of zinc [50,51,52,53,54]. Formula milk concentration of zinc is 1.5–6 mg/L [50,51,52,53,54]. Despite the greater concentration of zinc in formulas, net absorption was significantly improved with human milk as compared with formulas (60% vs. 20%) [50,51,52,53,54]. Absorption is slightly decreased in fortified preterm human milk as a percentage, although net absorption increases [50,51,52,53,54]. Endogenous fecal zinc losses are estimated to range between 50 and 150 mcg/kg per day [55,56]. The gastrointestinal tract is the major site of zinc losses, resulting from the secretion of endogenous zinc into the lumen and subsequent excretion in the feces. The amount of zinc excreted in the feces could be considered as a pool of rescue that could be reabsorbed and used according to host zinc status. However, the amount of zinc reabsorbed may also be influenced by the occurrence of pathological condition such as diarrhea and steatorrhea [55,56]. Urinary excretion of zinc is high in extremely preterm neonates (35 mcg/kg per day) in comparison with at term babies [55,57]. In the absence of adequate supplementation, serum zinc concentrations decline rapidly during the first months of life (Figure 3) [58,59,60,61].

A series of zinc transporter proteins (ZnT-1, ZnT-2, and ZnT-4) have been identified in the mammary gland [62]. In rare cases, the mammary gland may have a defect in the ZnT-4 gene, resulting in impaired secretion of zinc in breast milk. Breast milk zinc concentrations are below the normal range at all stages of lactation in these women [63]. Infants breast-fed by these mothers typically display the classic phenotype of acrodermatitis enteropathica already at approximately two months of postnatal age [63]. This syndrome has been described in term infants but is more likely to affect infants born preterm, suggesting an increased vulnerability of the preterm infant to clinically significant zinc deficiency syndromes [49]. Zinc concentrations in human milk may be influenced by vitamin A status, which regulates zinc transporters in the mammary gland (Table 4) [64,65,66,67,68,69,70,71,72,73,74]. In addition, the metabolism of zinc and vitamin A seems to be interrelated [72,74,75]. Severe vitamin A deficiency may reduce the absorption and lymphatic transport of zinc by altering synthesis of a zinc-dependent binding protein [75]. This aspect should be considered when zinc is supplemented in neonates receiving fortified human milk and multivitamin products containing vitamin A. These considerations suggest evaluating vitamin A supplementation, in addition to zinc supplementation, in neonates with evidence of zinc deficiency and in their mothers. However, the evidence of a strict zinc-vitamin A interaction in preterm neonates is still lacking.

Accurate biomarkers of zinc status are still lacking. Measurement of serum zinc concentrations remains the best—albeit imperfect—marker to identify zinc deficiency (Table 5) [76,77,78,79]. Based on the data obtained from cord blood at birth, it is reasonable to identify a condition of zinc deficiency with serum concentrations at birth below 55 mcg/dL (8.4 mcmol/L) [80]. Serum zinc levels measured in cord blood at birth are higher in preterm compared with at term neonates (Table 6) [81,82,83,84,85,86]. Figure 3 depicts serum levels of zinc in preterm neonates in the first 28 days of life [58,59,60,61]. In preterm neonates, serum zinc levels rapidly decline during the first month of life, so that, at post-conceptional age of 40 weeks, serum zinc concentrations may be lower in preterm neonates compared with term neonates [58,59,60,61].

Typical clinical manifestations are commonly observed only for conditions of severe zinc deficiency. Increasing data suggest significant subclinical effects of a moderate zinc deficiency in preterm neonate [87]. Thus, an increase in zinc supplementation should be considered in all neonates with reduced serum zinc concentrations.

Typical signs of zinc deficiency in newborns include dermatitis and growth impairment [88,89]. However, the zinc status in the first weeks of life may influence the occurrence of many other pathological conditions interfering with their crucial pathogenic steps.

Preterm infants are generally believed to be in a negative zinc balance within the first 4–8 weeks of life, unless intakes are not bolstered by specific supplements [122]. Zinc could be provided through parenteral nutrition support, or fortified human milk, formulas designed for premature infants, or specific products containing zinc. Zinc-supplemented parenteral nutrition early in postnatal life, followed by enteral administration of zinc in adequate doses, should aim to be sufficient to meet zinc requirements also for extremely low birth weight infants (ELBW). Several indications for zinc requirements are available (Table 7) [123,124,125,126,127,128,129,130]. Interestingly, recommended intakes have progressively increased during the last decade. The recommended enteral intake ranges between 0.8 to 3 mg/Kg/day [3]. Zinc requirements for term infants are estimated to be 0.8 mg/day, whereas preterm neonates may require up to 3 mg/kg per day to achieve adequate zinc retention [3]. Less variability regarding intravenous supplementation may be found in the recommendations of different scientific societies and committees. Despite that only 60% of parenterally infused zinc is retained, different authors suggest parenteral supplementation with 350 mcg/kg per day [51,131]. Recent evidence supports the use of higher zinc doses to improve survival and reduce morbidity in VLBW neonates [87]. Higher zinc supplementation is also justified if we consider that in the last trimester of pregnancy the fetus receives up to 1 mg/Kg/day of zinc from the mother. Thus, to reach a similar intake, 0.5–0.8 mg/Kg/day or 4–5 mg/Kg/day zinc should be administered by the parenteral or oral route, respectively (Figure 4) [132,133]. However, further trials, including pharmacokinetic studies, are advocated before modifying current recommendations on the use of zinc.

Zinc requirement in preterm neonates is quite similar to that of fetuses with similar postconceptional age. However, a lower percentage of zinc administered in preterm neonates by enteral or parenteral nutrition is retained. Thus, if zinc is provided according to current recommendation (columns zinc intake), the final balance of zinc is negative, at variance with what happens during fetal life, when zinc is transferred by the placenta, directly in the fetal circulation, at a daily amount of about 900 mcg.

Zinc supplementation is generally safe. However, an excess of zinc (>20 mg/Kg/day) may influence absorption and retention of other trace elements such as copper and vitamin A [50,74]. Zinc may induce copper deficiency by inhibiting the gastrointestinal absorption [134]. On the other hand, copper supplementation boosts the conjugation of zinc with large molecules and depletes the ratio of zinc coupled with smaller molecules, thereby suggesting an antagonism between the transport of these two elements [135]. Indeed, no cases of hypocupremia have been described in trials using zinc in neonates (with doses ranging from 2 to 10 mg/Kg/day) not even when copper was not supplemented.

Zinc status influences vitamin A absorption, transport and utilization [74]. Evidence of an effect of zinc intake on vitamin A status from animal experiments are inconclusive, mainly because of the use of inadequate control groups [136]. Randomized trials in children have failed to show a consistent effect of zinc supplementation on vitamin A status [137] and there is no such evidence in neonates. To the best of our knowledge, none of the other potential consequences of zinc excess, such as cytopenias or myeloneuropathy, has been reported in neonates.

Zinc plays a crucial role during the first phase of life, including embryogenesis and fetal life. Preterm neonates continue their “fetal” development in an extra-uterine environment. Consequently, zinc stores are not completed and its requirement increase in babies born prematurely. Considering the large number of roles played by zinc in early life, the consequences of zinc deficiency in preterm neonates are extremely variable and may be severe in many cases. A large percentage of preterm neonates is affected by mild to moderate subclinical zinc deficiency. Diagnosis of zinc deficiency, especially if of mild severity, is not easy due to its nonspecific features and to the lack of highly sensitive biomarkers. On the other hand, early diagnosis may be essential to avoid severe consequences of zinc deficiency. Clinical evaluation and research of the risk factors associated with the measurement of serum level of zinc is the most appropriate approach in the diagnosis of zinc deficiency. Dealing with the deficiency by zinc supplements is highly effective in neonates, with proven benefits on skin lesions and growth. Supplementation with adequate doses of zinc may also reduce the occurrence and severity of the morbidities typical of prematurity. However, current recommendations for zinc seem inadequate to meet the requirement of extremely preterm neonates and should be revised.

Despite the consistent number of articles on the role of zinc in early life, many interesting aspects remain to be clarified. Possible area of future research may be summarized in ten issues:

Study of the role of zinc in infertility and multiple abortions

When such data become available, the role of zinc in early life will be further clarified and the use of zinc in neonates could be optimized. Considering the critical role of zinc in neonatal life, research in this field is widely advocated.