Nitrofurantoin and Hemolytic Anemia: What You Need to Know About G6PD Deficiency Risk

Every year, millions of people take nitrofurantoin to treat a simple urinary tract infection. It works. It’s cheap. And for most people, it’s safe. But for a significant number - especially those with an undiagnosed genetic condition - this common antibiotic can trigger a life-threatening reaction: hemolytic anemia.

What Happens When Nitrofurantoin Meets G6PD Deficiency?

Nitrofurantoin isn’t just any antibiotic. It’s an oxidizing agent. In healthy people, red blood cells handle this just fine. They have a built-in defense system powered by an enzyme called glucose-6-phosphate dehydrogenase (G6PD). This enzyme keeps glutathione - the cell’s main antioxidant - in working order. Glutathione neutralizes harmful oxidants before they can damage hemoglobin and rupture red blood cells.

But in people with G6PD deficiency, that defense system is broken. Their red blood cells can’t make enough glutathione. When nitrofurantoin enters the bloodstream, it floods the system with oxidative stress. Hemoglobin starts to clump. Red blood cells swell, become brittle, and burst. This is hemolytic anemia - the sudden, rapid destruction of red blood cells.

Symptoms don’t wait. They show up fast: dark urine (like cola), extreme fatigue, jaundice (yellow skin or eyes), shortness of breath, rapid heartbeat, and sometimes fever or back pain. In severe cases, patients collapse from low blood pressure or kidney failure. A 2023 case report in the National Center for Biotechnology Information described a patient whose hemoglobin dropped from 13.2 g/dL to 6.8 g/dL in just 48 hours after starting nitrofurantoin. He was hospitalized. He didn’t need a transfusion. He just needed to stop the drug - and he recovered fully. But not everyone is that lucky.

Who’s at Risk?

G6PD deficiency isn’t rare. It affects an estimated 400 million people worldwide. But most don’t know they have it until they take a drug like nitrofurantoin, primaquine, or a sulfa antibiotic.

The risk isn’t evenly spread. It’s tied to geography and ancestry:

• 10-14% of people of African descent (including African Americans)
• 4-7% of people from the Mediterranean, Middle East, or North Africa
• 2-5% of people from Southeast Asia

In Australia, where an estimated 1 in 100 people carry the gene, many are from Southeast Asian or Middle Eastern backgrounds. Yet, screening isn’t routine. A 2022 survey of 350 primary care doctors found only 32% tested for G6PD deficiency before prescribing nitrofurantoin - even though the American Society of Hematology and the Clinical Pharmacogenetics Implementation Consortium (CPIC) have said for years: avoid it.

Why Is This Still a Problem?

Nitrofurantoin is still widely used because it’s effective against common UTI bugs like E. coli. Resistance to trimethoprim-sulfamethoxazole (TMP-SMX), another first-line drug, is rising. Nitrofurantoin keeps working where others fail. That’s why it still makes up about 18% of UTI prescriptions in the U.S.

But here’s the catch: the FDA label warns about hemolytic anemia in G6PD-deficient patients - but doesn’t require testing. No mandate. No checklist. No automated alert in most electronic health records. That’s a gap.

Doctors often assume: “If they don’t say they have it, they don’t have it.” But 50-60% of people with G6PD deficiency are undiagnosed until they have a crisis. A woman from Sydney with ancestry from Sri Lanka gets a UTI. She’s never been tested. She’s given nitrofurantoin. Three days later, she’s in the ER. That’s not a rare event. It’s predictable.

What Are the Alternatives?

You don’t need to risk it. There are safer options:

• Fosfomycin - a single-dose pill, safe in G6PD deficiency, effective for uncomplicated UTIs
• Cephalexin - a first-generation cephalosporin, low risk of hemolysis
• Pivmecillinam - used in Europe and Canada, not yet widely available in the U.S., but low oxidative risk
• Trimethoprim-sulfamethoxazole - also risky in G6PD deficiency, so avoid if you’re unsure

Fosfomycin is the best substitute. It’s not perfect - it doesn’t work for kidney infections - but for simple bladder infections, it’s just as effective as nitrofurantoin and carries zero risk of oxidative hemolysis.

What Should You Do?

If you’re prescribed nitrofurantoin, ask:

• “Do I have G6PD deficiency?”
• “What’s my ancestry? Am I from Africa, the Mediterranean, or Southeast Asia?”
• “Is there a safer alternative?”

If you’ve ever had unexplained jaundice, dark urine after taking medication, or a family history of anemia - get tested. A simple blood test takes 15 minutes. It costs between $35 and $50. A hospital stay for hemolytic anemia? That’s $8,500 to $12,000.

If you’re a healthcare provider: screen before you prescribe. Especially for patients of African, Mediterranean, or Southeast Asian descent. Use clinical decision support tools. If your EHR doesn’t flag G6PD risk, ask for it. Push for change.

What If I’m Pregnant or Have a Baby?

Pregnant women are at higher risk - not because pregnancy causes G6PD deficiency, but because they’re often treated for UTIs, and the baby might inherit the gene. There are documented cases of newborns developing hemolytic anemia after exposure to nitrofurantoin through the placenta or breast milk. The CPIC guidelines say: avoid nitrofurantoin in pregnancy if G6PD status is unknown. Fosfomycin is the go-to alternative.

Infants under one month shouldn’t get nitrofurantoin at all - their liver enzymes aren’t mature enough to handle it, even without G6PD deficiency. But if the mother has G6PD deficiency and takes nitrofurantoin while breastfeeding, the drug can pass into milk and trigger hemolysis in the baby.

What Do the Guidelines Really Say?

The most current guidance comes from the Clinical Pharmacogenetics Implementation Consortium (CPIC), updated in 2023:

• Do not use nitrofurantoin in patients with G6PD deficiency and chronic non-spherocytic hemolytic anemia (CNSHA).
• Avoid nitrofurantoin in patients with G6PD deficiency without CNSHA - use alternatives.
• Consider testing before prescribing in high-risk populations.

The American Society of Hematology is even clearer: “Nitrofurantoin should be avoided in patients with known G6PD deficiency.”

Yet, in practice, many doctors still prescribe it. Why? Because they don’t know. Or they think the risk is too low. But 42 confirmed cases of nitrofurantoin-induced hemolysis in G6PD-deficient patients were documented in a single 2022 review. Ten of those were fatal.

The Bigger Picture

This isn’t just about one drug. It’s about how medicine treats genetic risk. We test for allergies. We check liver function. We monitor kidney health. But we rarely ask: “Do you have G6PD deficiency?”

Point-of-care G6PD tests are now available - a drop of blood, a handheld device, results in 10 minutes. They’re not in every clinic yet, but they’re coming. The NIH is running a trial to see if routine testing before nitrofurantoin use saves money and lives. Early data suggests it does.

The global market for G6PD testing is growing fast - from $185 million in 2022 to an expected $310 million by 2027. That growth isn’t just about nitrofurantoin. It’s about recognizing that genetic risk isn’t rare. It’s routine.

Bottom Line

Nitrofurantoin is a useful tool. But it’s not for everyone. If you’re prescribed this antibiotic and you’re of African, Mediterranean, or Southeast Asian descent - ask for a G6PD test. If you’ve ever had unexplained anemia, jaundice, or dark urine after taking medicine - get tested. If you’re a clinician - screen before you prescribe. There are safe alternatives. The cost of testing is tiny compared to the cost of a hospital stay. And the risk of missing it? It’s not worth it.