Zinc (Zn) is an essential trace element second only to iron in abundance and biological importance. It plays critical roles in enzymatic activity, gene expression, cellular integrity, immune regulation, skeletal growth, and neurodevelopment. During gestation, zinc supports cellular proliferation and neuronal maturation, with fetal accretion peaking in the third trimester. Preterm infants, who miss this late-gestation transfer, are uniquely predisposed to deficiency, compounded by high metabolic demands, renal and gastrointestinal immaturity, increased urinary and gastrointestinal losses, and comorbidities such as bronchopulmonary dysplasia or necrotizing enterocolitis. While breast milk provides highly bioavailable zinc, its concentrations decline over time, and preterm milk, although more bioavailable than formula, contains less absolute zinc. Deficiency in preterm infants can manifest as dermatologic and oral lesions, diarrhea, growth failure, alopecia, and impaired immunity. Diagnostic challenges stem from reliance on serum zinc levels, which reflect only a fraction of total body zinc, although reductions in alkaline phosphatase and altered copper metabolism may provide additional insights.

Evidence supports zinc supplementation in preterm and low birthweight infants, with doses exceeding 3 mg/kg/day associated with improved growth, head circumference, and reduced morbidity, including lower rates of sepsis, bronchopulmonary dysplasia, and necrotizing enterocolitis. Multiple zinc salts are bioavailable, with citrate and bisglycinate showing superior palatability and absorption. While supplementation is generally safe, excessive zinc can interfere with copper homeostasis and lead to hematologic and neurologic complications, highlighting the importance of biochemical monitoring.

Zinc is thus a critical micronutrient in neonatal care, and targeted supplementation offers both short- and long-term benefits for high-risk preterm infants. Early recognition of deficiency, careful dosing, and vigilant monitoring are essential to optimizing outcomes while avoiding trace element imbalances.

• Zinc
• Infant
• Premature
• Micronutrients
• Zinc Deficiency
• Infant Nutrition Disorders
• Dietary Supplements

Bharti D, Bharti M (2025) Zinc and its Role in Preterm Infant Nutrition and Development. Arch Paediatr Dev Pathol 8(1): 1029.

Zinc (Zn) is the second most abundant trace element after iron and is indispensable for a wide range of physiological processes, including enzymatic activity, cell signaling, gene transcription, tissue integrity, immune function, skeletal growth, and neurodevelopment [1]. Because it cannot be synthesized by the human body, zinc must be obtained through diet or supplementation [2]. During early gestation, zinc supports cell division and differentiation, while in later fetal stages it contributes to neuronal development and enzymatic regulation. Fetal zinc accretion peaks in the third trimester, which makes preterm infants particularly vulnerable to deficiency due to incomplete placental transfer.

Zinc absorption occurs primarily in the distal duodenum and proximal jejunum, facilitated by the 

ZIP4 (SLC39A4) transporter, which mediates entry into enterocytes, and ZnT-1 (SLC30A1), which exports zinc into plasma. In circulation, zinc is largely protein-bound, with approximately 60% attached to albumin and 30% to alpha-2-macroglobulin. Storage occurs mainly in the liver, pancreas, and intestinal mucosa, with less dynamic reserves in bone and muscle. Only about one percent of total body zinc is present in plasma at any time, and excretion is primarily fecal, with smaller contributions from urine and sweat.

Serum zinc concentration, with a reference range of 74– 146 µg/dL, remains the most widely used biomarker for deficiency, though it reflects only a fraction of total body zinc [3]. A decline in alkaline phosphatase activity is also a useful indicator and may provide more meaningful insight into functional zinc status [4]. Deficiency is frequently associated with altered copper metabolism, reflected 

in hypercupremia and an elevated Cu:Zn ratio [5], while reductions in insulin-like growth factor-1 have also been reported [6], though interpretation is complicated by concurrent hormonal or systemic illnesses.

Preterm infants are at particularly high risk for zinc deficiency due to a convergence of factors: the loss of third- trimester placental transfer, lower zinc concentrations in breast milk, increased metabolic demands from rapid growth and respiratory support, renal immaturity with urinary zinc wasting, and gastrointestinal immaturity impairing absorption [7,8]. Additional losses may occur through feeding tubes and central lines. Clinical comorbidities such as bronchopulmonary dysplasia, necrotizing enterocolitis, or surgical conditions like gastroschisis can further disrupt zinc balance. Medications including diuretics and corticosteroids increase urinary zinc loss [9], while nutritional interactions also play a role; casein and phytates bind zinc and reduce absorption [10], whereas amino acids, medium-chain triglycerides, and citrate enhance it.

Breast milk remains the most effective zinc source for infants. Colostrum contains the highest zinc concentrations, which decline steadily over the course of lactation [11]. Although preterm breast milk contains less total zinc than term milk, its bioavailability is substantially higher, reaching 50–60% compared with 14–24% from formula. Fortification of breast milk enhances zinc content, with liquid fortifiers providing greater increases than powder forms [12]. Donor human milk serves as an alternative when maternal milk is unavailable, although pasteurization can impair zinc absorption. By contrast, formula compensates for reduced bioavailability with higher zinc concentrations, but absorption is limited to approximately 30% due to casein binding, and high dietary iron may further inhibit uptake. Among supplemental forms, zinc citrate, sulfate, acetate, and gluconate are all well absorbed, though zinc citrate demonstrates the best palatability and bioavailability [13].

Zinc deficiency in preterm infants can arise from both acquired and genetic causes. Acquired deficiency is more common and is typically related to inadequate intake, malabsorption, or prolonged parenteral nutrition. Mild-to- moderate maternal zinc deficiency, which is widespread globally, is associated with intrauterine growth restriction and an increased risk of preterm birth. A Cochrane review concluded that maternal zinc supplementation may modestly reduce preterm birth risk but does not significantly affect birth weight unless initiated before 27 weeks of gestation [14]. Rare genetic causes include acrodermatitis enteropathica, an autosomal recessive condition caused by SLC39A4 mutations affecting the ZIP4 transporter, and mutations in the ZnT2 transporter (SLC30A2), which impair zinc secretion into breast milk [15].

Clinical manifestations of deficiency usually emerge by approximately three months of age and range from subtle to multisystem involvement. Dermatologic features include erythematous, scaly plaques around the mouth, extremities, and diaper region, which may progress to vesicles, pustules, erosions, or hyperkeratosis and often follow a periorificial or acral distribution. Oral manifestations include glossitis, angular stomatitis, and aphthous ulcers, with secondary colonization by Candida or Staphylococcus aureus being common. Systemic signs include chronic diarrhea, irritability, anorexia, growth failure, alopecia, and impaired immune function leading to recurrent infections.

Therapeutic zinc supplementation supports somatic growth, neurodevelopment, and immune defense. Clinical trials have shown that doses above 3 mg/kg/day are associated with significant increases in weight, length, and head circumference, while high-dose supplementation in very low birthweight infants has been linked to reduced incidence of sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity. Recommended enteral doses for preterm infants are 1–3 mg/kg/day, with zinc citrate preferred for its palatability and bisglycinate for superior bioavailability. For parenteral nutrition, a dose of 0.4–0.5 mg/kg/day is advised. Infants with acrodermatitis enteropathica typically require 5–10 mg/kg/day of oral zinc sulfate, which can rapidly reverse symptoms.

Although zinc is generally well tolerated, excessive intake can impair copper absorption through upregulation of metallothionein, which binds copper preferentially, potentially leading to anemia, neutropenia, or neurological complications. Acute toxicity is rare but may present with vomiting, abdominal pain, and diarrhea, and a fatal case has been reported following a parenteral overdose [16]. Regular monitoring of serum zinc, alkaline phosphatase, serum copper, ceruloplasmin, and complete blood count is therefore essential during supplementation.

In conclusion, zinc is a crucial micronutrient for growth, immune regulation, and neurological development. Preterm infants are uniquely vulnerable to deficiency due to their dependence on late-gestation zinc transfer and increased metabolic requirements. Early recognition and carefully tailored supplementation, coupled with close biochemical monitoring, are essential to optimize both short- and long-term outcomes. With appropriate management, zinc supplementation in this high-risk population provides significant benefits while minimizing the risk of trace element imbalances.

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