As a commonly used oral iron supplement in clinical practice, ferrous gluconate is widely applied in the prevention and treatment of iron deficiency anemia (IDA) and as a food nutrient fortifier (e.g., in infant formula, cereal products) due to its good water solubility and low gastrointestinal irritation. Despite its high safety profile, the risk of allergic reactions cannot be ignored. These reactions are mostly associated with abnormal individual immune responses; although the incidence is low (approximately 0.1%–0.5%), severe cases may lead to anaphylactic shock, a life-threatening condition. This article analyzes the clinical manifestations and triggers of ferrous gluconate allergic reactions through typical cases, and proposes targeted prevention strategies based on clinical practice and food application scenarios to provide references for its safe use.

I. Clinical Features and Typical Cases of Ferrous Gluconate Allergic Reactions

Ferrous gluconate allergic reactions belong to Type I hypersensitivity (immediate hypersensitivity), primarily triggered by the "ferrous ion" or "gluconate moiety" in its molecular structure, which abnormally activates the body’s immune system and releases inflammatory mediators such as histamine and leukotrienes, causing local or systemic symptoms. Clinical symptoms are classified as mild, moderate, or severe, and typically occur within minutes to 24 hours after medication administration or consumption. Specific features and cases are as follows:

(I) Mild Allergic Reactions: Localized Symptoms, Easily Overlooked

Mild allergic reactions are the most common, mainly presenting as localized discomfort of the skin or mucous membranes. Symptoms are mild and short-lived (lasting hours to 1 day), often mistaken for "drug irritation" or "skin sensitivity." Typical symptoms include:

Skin symptoms: Scattered urticaria (wheals), pruritus, and erythema (mostly on the face and limbs), without obvious swelling.

Mucous membrane symptoms: Mild oral mucosal pruritus and lip swelling (angioedema), without dyspnea or dysphagia.

Case 1: A 32-year-old female patient with IDA (hemoglobin: 95g/L) took oral ferrous gluconate tablets (0.3g, three times daily). On the 3rd day of medication, she developed scattered wheals on her forearms accompanied by pruritus, with no other discomfort. Symptoms resolved spontaneously 1 day after drug withdrawal. Allergen testing (skin prick test) showed a positive result for ferrous gluconate, confirming a mild allergy. She was later switched to iron polysaccharide complex (a non-ionic iron supplement) without further allergic reactions.Trigger analysis: The patient had a history of pollen allergy (atopic constitution), and her immune system was sensitive to ferrous ions in ferrous gluconate, triggering local mast cells to release histamine and cause skin symptoms.

(II) Moderate Allergic Reactions: Initial Systemic Symptoms, Requiring Timely Intervention

Moderate allergic reactions involve multiple systemic systems, with more obvious symptoms than mild reactions. Without timely management, they may progress to severe reactions. Typical symptoms include:

Skin symptoms: Generalized urticaria, diffuse erythema, and obvious skin swelling (e.g., eyelid, facial edema).

Respiratory symptoms: Mild cough, nasal congestion, and rhinorrhea, without significant dyspnea.

Gastrointestinal symptoms: Nausea, vomiting, and abdominal pain (non-spasmodic pain caused by gastrointestinal irritation, often accompanied by bloating).

Case 2: A 5-year-old child with iron deficiency (serum ferritin: 12μg/L) due to inadequate complementary feeding consumed ferrous gluconate-fortified cereal powder (5mg iron/100g, once daily). On the 5th day of consumption, the child developed generalized wheals, eyelid edema, mild cough, and vomiting. The cereal was immediately discontinued, and the child was given oral loratadine (5mg, pediatric dose). Symptoms completely resolved after 2 days. Allergen testing showed positive IgE antibodies to ferrous gluconate, ruling out other food allergens (e.g., milk, eggs).Trigger analysis: The child’s immune system was immature, resulting in low tolerance to iron supplements. Additionally, ferrous gluconate in the fortified cereal may have had a "synergistic sensitization" effect with other components (e.g., gluten), exacerbating the allergic reaction.

(III) Severe Allergic Reactions: Anaphylactic Shock as the Main Manifestation, Life-Threatening

Severe allergic reactions (anaphylactic shock) have an extremely low incidence (approximately 0.01%) but onset rapidly and progress quickly. Without emergency treatment within 1 hour, the mortality rate is high. Typical symptoms center on circulatory and respiratory failure, accompanied by multi-organ involvement:

Circulatory system: A sudden drop in blood pressure (systolic blood pressure <90mmHg), tachycardia (>120 beats/min), cold and clammy extremities, and pale complexion.

Respiratory system: Laryngeal edema, dyspnea, wheezing (bronchospasm), and severe cases may progress to respiratory failure.

Nervous system: Confusion, dizziness, syncope, and restlessness in some patients.

Case 3: A 28-year-old male patient with chronic blood loss (hemorrhoidal bleeding) took oral ferrous gluconate oral solution (10mL, 30mg iron/10mL, twice daily). Fifteen minutes after administration, he suddenly developed laryngeal edema, dyspnea, dizziness, and a drop in blood pressure to 80/50mmHg, confirming anaphylactic shock. Emergency measures were immediately initiated: intramuscular injection of epinephrine (0.3mg), oxygen therapy, and intravenous infusion of dexamethasone (10mg). His blood pressure returned to normal and dyspnea relieved 30 minutes later, and he was discharged after 2 days of hospital observation. Subsequent testing revealed the patient was highly sensitive to "ferrous ions" and had a history of β-lactam antibiotic allergy, placing him in a high-risk allergy group.Trigger analysis: The patient had a highly atopic constitution. Ferrous ions in ferrous gluconate rapidly activated specific IgE antibodies in the body, triggering massive release of inflammatory mediators from mast cells and basophils, leading to systemic vasodilation, laryngeal edema, and anaphylactic shock.

II. Core Triggers of Ferrous Gluconate Allergic Reactions

Ferrous gluconate allergic reactions are not caused by a single factor but result from the combined effects of "individual constitution, drug/food properties, and usage patterns." Core triggers can be categorized into three types:

(I) Individual Factors: Atopic Constitution and Immune Status as the Basis

Atopic constitution: Individuals with a clear history of allergies (e.g., drug allergies: penicillins, cephalosporins; food allergies: milk, seafood; environmental allergies: pollen, dust mites) have an "overly sensitive immune system." They are prone to abnormal immune responses to components in ferrous gluconate (ferrous ions, gluconate moiety), with an allergy risk 5–10 times higher than that of the general population.

Abnormal immune function: Infants (immature immune system), the elderly (declined immune function), and patients with immunodeficiency (e.g., long-term use of immunosuppressants) have impaired ability to recognize "foreign substances." They may misidentify ferrous gluconate as a "harmful substance," triggering allergic reactions.

Genetic factors: Some individuals have inherited immune disorders such as "mast cell activation syndrome," resulting in unstable mast cells in the body. Even low-dose exposure to ferrous gluconate may trigger massive release of inflammatory mediators, leading to allergies.

(II) Drug/Food Properties: Potential Impacts of Components and Dosage Forms

Sensitization of ferrous ions: Divalent ferrous ions (Fe²⁺) in ferrous gluconate are one of the core allergens. Fe²⁺ has strong redox activity and may bind to proteins in the body to form a "hapten-carrier complex," activating T cells and B cells to produce specific IgE antibodies—laying the groundwork for subsequent allergic reactions.

Synergistic effect of excipients: Excipients in oral iron supplements or fortified foods (e.g., fillers: microcrystalline cellulose; binders: hypromellose; colorants: tartrazine) may have "synergistic sensitization" with ferrous gluconate. For example, tartrazine itself has mild sensitizing properties; when entering the body together with Fe²⁺, it enhances immune system activation and increases allergy risk.

Differences in dosage forms: Ferrous gluconate in oral solution form dissolves rapidly, releasing Fe²⁺ quickly and resulting in high concentrations in the body over a short period. Allergic reactions may occur faster (within minutes to 1 hour). In contrast, tablet/capsule forms release the drug slowly, so allergic reactions may be delayed (6–24 hours) with relatively mild symptoms.

(III) Usage Patterns: Improper Dosage and Combined Application

Excessive dosage: Overdose (e.g., adults taking more than 1.5g of ferrous gluconate orally daily) increases the accumulation of Fe²⁺ in the body, raising the probability of interaction with the immune system. Allergy risk increases with dosage. For example, some patients double their medication dose to "replenish iron quickly," which may induce moderate to severe allergies.

Combined medication/consumption: Concurrent use with other potentially sensitizing drugs (e.g., non-steroidal anti-inflammatory drugs: ibuprofen) or foods (e.g., seafood, mangoes) increases the body’s immune burden and causes additive allergic effects. For example, consuming seafood while taking ferrous gluconate may worsen allergic symptoms from "skin pruritus" to "laryngeal edema."

Lack of allergy testing: For high-risk populations (e.g., history of iron supplement allergy), failure to conduct a small-dose test or allergen detection before initial use of ferrous gluconate, and direct use of the regular dose, may trigger severe allergic reactions.

III. Prevention Strategies for Ferrous Gluconate Allergic Reactions

Targeting the triggers of ferrous gluconate allergic reactions, a prevention system should be established covering three stages: "pre-use assessment, in-use monitoring, and post-allergy management," encompassing both clinical medication and food fortification scenarios to minimize risks.

(I) Pre-Use Prevention: Risk Assessment and Allergy Testing

1. Comprehensive Individual Risk Assessment

Before medication administration/consumption, thoroughly inquire about the patient’s allergy history (drug, food, environmental allergies), past iron supplement use (e.g., whether discomfort occurred after taking ferrous sulfate or ferrous fumarate), and underlying diseases (e.g., immunodeficiency, mast cell activation syndrome).

For high-risk populations such as infants, the elderly, and individuals with atopic constitutions, prioritize "low-sensitization iron supplements" (e.g., iron polysaccharide complex, ferrous zinc gluconate oral solution—where Fe²⁺ exists in a chelated form with lower sensitization). If ferrous gluconate must be used, strictly control the dosage.

2. Allergy Testing for High-Risk Populations

Individuals with a history of iron supplement allergy or severe atopy should undergo a "small-dose test" before initial use: adults take 1/10 of the regular dose (e.g., 0.03g for a regular 0.3g dose), and children take a weight-based dose (0.5mg/kg). Observe for 24 hours; if no symptoms (e.g., rash, pruritus, dyspnea) occur, gradually increase to the regular dose.

When conditions permit, conduct allergen testing (skin prick test, serum-specific IgE test) to confirm sensitivity to ferrous gluconate or its excipients, avoiding blind use.

(II) In-Use Prevention: Dosage Control and Real-Time Monitoring

1. Strict Dosage and Course Control

Adhere to the principle of "individualized dosage": the regular adult dose is 0.9–1.2g daily (divided into 3 doses), and the pediatric dose is 30mg/kg daily (divided into 2–3 doses), avoiding overdose.

In food fortification scenarios, comply with national standards (e.g., GB 14880-2012 National Food Safety Standard for the Use of Food Nutrient Fortifiers specifies that the addition of ferrous gluconate in infant formula should be 3.0–14.0mg/100g). Do not add excessive amounts, and clearly label packages with "contains iron supplement, use with caution in individuals with allergies."

2. Real-Time Monitoring of Physical Reactions

Within 1 hour (especially for oral solutions) and 24 hours (for tablets/capsules) after medication administration/consumption, closely monitor for symptoms such as skin pruritus, rash, dyspnea, and abdominal pain. Discontinue use immediately if any symptoms occur.

Infants cannot express discomfort clearly; focus on observing "abnormal manifestations" (e.g., persistent crying, facial swelling, refusal to eat, rapid breathing) to avoid risk escalation due to overlooked symptoms.

3. Avoid Improper Combined Use

During ferrous gluconate administration, avoid concurrent use of non-steroidal anti-inflammatory drugs and antihistamines (which may mask early allergic symptoms), and avoid consuming highly allergenic foods such as seafood, mangoes, and pineapples.

If combined use with other drugs (e.g., vitamin C, which promotes Fe²⁺ absorption) is necessary, consult a doctor or pharmacist to confirm no synergistic sensitization risk before use.

(III) Post-Allergy Management: Graded Response and Follow-Up Care

Mild allergic reactions: Discontinue ferrous gluconate immediately; no special treatment is required, as symptoms usually resolve spontaneously within 1–2 days. If pruritus is severe, oral non-sedating antihistamines (e.g., loratadine, cetirizine) can be used to avoid skin infection from scratching.

Moderate allergic reactions: After discontinuation, administer oral antihistamines (10mg loratadine for adults, 5mg for children) and monitor changes in respiration and blood pressure. If eyelid edema or mild cough occurs, seek medical attention promptly; intravenous glucocorticoids (e.g., 5–10mg dexamethasone) may be necessary to prevent symptom progression.

Severe allergic reactions (anaphylactic shock): Immediately initiate emergency procedures: ① Administer intramuscular epinephrine (0.3–0.5mg for adults, 0.01mg/kg for children), which can be repeated every 5–10 minutes; ② Maintain airway patency and provide oxygen therapy (oxygen flow: 5–10L/min); if laryngeal edema is severe, perform endotracheal intubation or tracheotomy; ③ Administer intravenous normal saline for volume expansion to correct hypotension, and concurrently give 10–20mg dexamethasone intravenously; ④ After emergency treatment, transfer the patient to the ICU for 24–48 hours of observation and monitor vital signs.

Follow-Up Care

After allergic reactions subside, record the "allergen (ferrous gluconate), onset time, symptoms, and management measures" in the individual’s health record. For subsequent iron supplementation, clearly inform doctors or dietitians of the "ferrous gluconate allergy history" and select non-sensitizing iron supplements to avoid re-exposure to the allergen.

Although the incidence of ferrous gluconate allergic reactions is low, there is a risk of progression from mild skin symptoms to severe anaphylactic shock. Core triggers are related to individual atopic constitution, drug/food properties, and usage patterns. Prevention should focus on "pre-emptive risk assessment, real-time monitoring during use, and graded management after allergies." Particularly for high-risk populations such as infants, the elderly, and individuals with atopic constitutions, strict dosage control, small-dose testing, and avoidance of improper combined use are essential. In clinical and food applications, a balance between "iron supplementation efficacy" and "safety risk" should be struck. Through scientific prevention strategies, the safe application of ferrous gluconate in the prevention and treatment of IDA and food nutrient fortification can be ensured, reducing health hazards caused by allergic reactions.