What are the adverse effects and teratogenicity risks of nitrofurantoin (antibiotic)?

Nitrofurantoin Adverse Effects and Teratogenicity

Teratogenicity and Use in Pregnancy

Nitrofurantoin has no apparent adverse effects on the developing fetus and can be used safely in pregnant women for treatment of asymptomatic bacteriuria and urinary tract infections. 1

• Nitrofurantoin is a preferred agent during pregnancy due to its safety profile, along with β-lactam antimicrobials (ampicillin or cephalexin). 2
• Treatment duration in pregnancy should be 4-7 days rather than single-dose therapy, as single-dose regimens are less effective and associated with lower birth weight (RR 1.65,95% CI 1.06-2.57). 2
• Standard dosing is 100 mg twice daily for 5-7 days. 3
• Despite known pulmonary toxicity in non-pregnant patients, nitrofurantoin-induced pulmonary reactions during pregnancy are extremely rare, with only isolated case reports in the literature. 4

Common Adverse Effects

Gastrointestinal symptoms are the most frequent adverse effects and are dose-related:

• Nausea, vomiting, and anorexia occur most commonly. 5
• Abdominal pain and diarrhea are less common. 5
• These reactions can be minimized by dose reduction. 5
• Sialadenitis, pancreatitis, and pseudomembranous colitis have been reported rarely. 5

Non-severe adverse effects occur more frequently with nitrofurantoin compared to other antibacterials (RR 2.24,95% CI 1.77-2.83). 6

Serious Pulmonary Adverse Effects

Acute pulmonary reactions are uncommon but potentially life-threatening, occurring in approximately 1 in 5,000 patients after first exposure. 7

Acute Pulmonary Reactions

• Occur at extremely low rates (0.001%) according to the American Urological Association. 3
• Typically manifest within the first week of treatment with fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with consolidation or pleural effusion, and eosinophilia. 5
• These reactions are believed to be immune-mediated rather than dose-dependent. 4
• Symptoms are reversible with immediate cessation of therapy, often with dramatic resolution. 5
• Recurrent reactions can occur upon re-challenge, even after previous episodes. 7
• EKG changes (non-specific ST/T wave changes, bundle branch block) and rarely cyanosis have been reported. 5

Chronic Pulmonary Reactions

• Can involve irreversible pulmonary fibrosis if not recognized early. 3, 4
• Risk increases with duration of prophylactic use. 6
• If symptoms are not recognized as drug-related and therapy continues, symptoms may become more severe. 5

Critical pitfall: Pulmonary symptoms are often misdiagnosed as pneumonia or other respiratory infections, potentially delaying discontinuation and subjecting patients to unnecessary treatments. 7, 8 Patients may present with elevated procalcitonin and C-reactive protein mimicking bacterial sepsis. 8

Serious Hepatic Adverse Effects

Hepatic reactions occur at extremely low rates (0.0003%). 3

• Include hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis. 5
• Laboratory abnormalities: increased AST, increased ALT. 5

Neurologic Adverse Effects

Peripheral neuropathy is a serious, potentially irreversible complication with reported fatalities. 5

Risk Factors for Peripheral Neuropathy:

• Renal impairment (creatinine clearance <60 mL/min or elevated serum creatinine) 5
• Anemia 5
• Diabetes mellitus 5
• Electrolyte imbalance 5
• Vitamin B deficiency 5
• Debilitating diseases 5

Other Neurologic Effects:

• Asthenia, vertigo, nystagmus, dizziness, headache, drowsiness 5
• Rarely: benign intracranial hypertension (pseudotumor cerebri), confusion, depression, optic neuritis, psychotic reactions 5
• Bulging fontanels in infants (rare) 5

Hematologic Adverse Effects

• Cyanosis secondary to methemoglobinemia (rare) 5
• Glucose-6-phosphate dehydrogenase deficiency anemia 5
• Eosinophilia, agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, megaloblastic anemia 5
• Most hematologic abnormalities resolve following cessation of therapy 5
• Aplastic anemia reported rarely 5

Dermatologic and Allergic Reactions

• Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson syndrome) reported rarely 5
• Transient alopecia 5
• Lupus-like syndrome associated with pulmonary reactions 5
• Angioedema, maculopapular/erythematous/eczematous eruptions, pruritus, urticaria, anaphylaxis 5
• Arthralgia, myalgia, drug fever, chills, vasculitis 5
• Hypersensitivity reactions represent the most frequent spontaneously-reported adverse events in worldwide postmarketing experience. 5

Monitoring During Prophylactic Use

For prophylactic use (typically 6-12 months, though some patients require longer periods), regular assessment for adverse effects is necessary. 3

• Severe adverse effects in cohort studies occur at frequencies of 0.02-1.5 per 1,000 nitrofurantoin users 6
• Risk of severe toxicity increases with duration of prophylaxis 6

Contraindications

Nitrofurantoin is contraindicated in patients with renal insufficiency as it does not achieve therapeutic concentrations and increases risk of toxicity. 1