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

Imagine you're prescribed nitrofurantoin for a stubborn urinary tract infection. You take it as directed, but two days later, you feel dizzy, your skin turns yellow, and your urine looks dark. You didn't know you had G6PD deficiency - and now, your red blood cells are breaking down. This isn't rare. It happens more often than most doctors admit.

What Is Nitrofurantoin, and Why Is It Used?

Nitrofurantoin, sold under brand names like Macrobid and Furadantin, is an antibiotic used almost exclusively for simple urinary tract infections (UTIs). It works by attacking bacteria in the urine, not the bloodstream. That’s why it’s safe for most people - it doesn’t linger in the body long enough to cause widespread harm. It’s cheap, effective, and has low resistance rates compared to other UTI drugs like trimethoprim-sulfamethoxazole.

But here’s the catch: nitrofurantoin is also one of the most common drugs to trigger hemolytic anemia in people with G6PD deficiency. And that’s not a small risk. Around 400 million people worldwide have this genetic condition, mostly in African, Mediterranean, Middle Eastern, and Southeast Asian populations. In the U.S., about 1 in 10 Black men and 1 in 14 Black women carry the gene. Yet, most doctors don’t test for it before prescribing.

What Is G6PD Deficiency?

G6PD stands for glucose-6-phosphate dehydrogenase. It’s an enzyme your red blood cells need to protect themselves from oxidative stress. Think of it like a shield. When you take certain drugs - like nitrofurantoin, sulfonamides, or primaquine - they create free radicals that damage red blood cells. Normally, G6PD helps neutralize those radicals. But if you’re deficient, your shield is broken. The cells burst, and hemoglobin leaks into your blood and urine.

This isn’t theoretical. In 1956, a case report in JAMA first linked nitrofurantoin to hemolytic anemia. Since then, over 300 documented cases have been published. Of those, 42 were confirmed in G6PD-deficient patients. Ten ended in death. Many more went unreported because the connection wasn’t made.

How Does Nitrofurantoin Cause Hemolytic Anemia?

Nitrofurantoin gets activated in the acidic environment of the bladder to kill bacteria. But in your bloodstream, it can also create oxidative stress. In people with normal G6PD levels, this is no problem. Their red blood cells have enough glutathione - a natural antioxidant - to clean up the damage.

In G6PD-deficient people, glutathione levels drop fast. Red blood cells can’t repair themselves. Hemoglobin clumps together, forming Heinz bodies. The spleen sees these damaged cells and destroys them. That’s hemolysis. You lose red blood cells faster than your bone marrow can replace them. Your hemoglobin plummets. Your bilirubin spikes. Your skin yellows. You feel weak, feverish, short of breath.

Onset is fast - usually within 24 to 72 hours of starting the drug. Labs show low haptoglobin, high LDH, high reticulocytes. The worst drop in hemoglobin happens around day 3 to 5. Most patients recover within 48 hours of stopping the drug, but some need hospitalization. A few need transfusions.

Who’s at Risk?

You’re at higher risk if you’re:

• Of African, Mediterranean, Middle Eastern, or Southeast Asian descent
• Male (since G6PD deficiency is X-linked)
• Have a family history of jaundice or anemia after taking certain drugs
• Are pregnant (nitrofurantoin crosses the placenta - and newborns can be affected)
• Have a history of unexplained jaundice as a baby

Here’s the scary part: 50 to 60% of people with G6PD deficiency don’t know they have it until they have a hemolytic crisis. No one tests newborns routinely in the U.S. unless they’re in a high-risk group. Many adults never get screened.

What Do Guidelines Say?

The American Society of Hematology says: “Avoid nitrofurantoin in patients with known G6PD deficiency.”

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is even more specific. They say:

• If you have G6PD deficiency without chronic hemolytic anemia - use nitrofurantoin with caution, only if no alternatives exist.
• If you have G6PD deficiency with chronic hemolytic anemia - do not use nitrofurantoin at all.

Yet, a 2022 survey of 350 U.S. primary care doctors found only 32% routinely check G6PD status before prescribing nitrofurantoin. Why? Because it’s not mandatory. The FDA label warns about the risk but doesn’t require testing. Most doctors assume the patient is fine unless they say otherwise.

What Are the Alternatives?

If you’re at risk, there are safer options:

• Fosfomycin - A single-dose oral antibiotic. Safe in G6PD deficiency. Often used in pregnant women.
• Pivmecillinam - Available in Europe, not yet in the U.S., but low risk for hemolysis.
• Cephalexin - A first-generation cephalosporin. Doesn’t cause oxidative hemolysis.
• Amoxicillin-clavulanate - Good for UTIs, low risk for G6PD patients.

Trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used, but it also carries a hemolytic risk - though lower than nitrofurantoin. Fluoroquinolones like ciprofloxacin are effective but come with their own side effects, including tendon damage and nerve issues. So, no perfect option - but there are safer ones.

Cost vs. Risk: Should You Get Tested?

G6PD testing costs $35 to $50. A hospital stay for hemolytic anemia? $8,500 to $12,000. That’s not even counting missed work, pain, or the trauma of nearly dying.

If you’re from a high-risk ethnic group, have a family history, or have ever had unexplained jaundice - get tested. It’s a simple finger-prick blood test. Results come back in hours. Many urgent care centers and community clinics offer it now.

Some hospitals are starting to build alerts into their electronic systems. If you’re Black, Mediterranean, or Southeast Asian and you’re prescribed nitrofurantoin, the system should pop up: “Check G6PD status.” But that’s still rare.

Real Cases, Real Consequences

A 32-year-old woman from Nigeria, living in London, took nitrofurantoin for a UTI. Two days later, she collapsed. Her hemoglobin dropped from 13 to 7.5 g/dL. Her bilirubin was over 10. She was hospitalized. She didn’t know she had G6PD deficiency. Her mother had jaundice after taking sulfa drugs in the 1970s. No one ever told her.

She recovered after stopping the drug and getting IV fluids. No transfusion needed. But she was lucky.

In another case, a 7-month-old baby developed severe anemia after his mother took nitrofurantoin while breastfeeding. The baby’s hemoglobin crashed. He needed a transfusion. His G6PD test came back positive.

These aren’t outliers. They’re preventable.

The Bigger Picture

Nitrofurantoin isn’t going away. It’s cheap, effective, and works against resistant bacteria. But its use needs to change. We’re in the age of precision medicine. We test for BRCA genes before giving certain chemo drugs. We screen for HLA-B*5701 before prescribing abacavir. Why not test for G6PD before giving nitrofurantoin?

The global market for G6PD testing is expected to hit $310 million by 2027. That’s because awareness is rising. But until testing becomes standard - especially for high-risk populations - people will keep getting hurt.

If you’re prescribed nitrofurantoin and you’re from a population with high G6PD prevalence - ask: “Have you checked my G6PD status?” If the answer is no, ask for an alternative. Or get tested before you start.

One test. One question. Could save your life.