Premenopausal patients with iron deficiency may require treatment even when they do not meet standard hemoglobin thresholds for anemia, but physicians may differ on how aggressively to investigate gastrointestinal causes and when to escalate to intravenous iron, according to a case-based Grand Rounds discussion published in Annals of Internal Medicine.
The discussion focused on Ms. B, a 35-year-old woman with heavy menstrual bleeding, microcytosis, and iron deficiency. Her laboratory findings included a hemoglobin level of 12.2 g/dL, mean corpuscular volume of 74 fL, ferritin level of 23 μg/L, and transferrin saturation of 6.4%. Although she did not meet the standard hemoglobin threshold for anemia in nonpregnant women, the discussants agreed that her iron deficiency warranted treatment.
The article reviewed recommendations from the 2020 American Gastroenterological Association guideline and the 2025 Iron Consortium evidence-based and expert consensus recommendations. The discussants, Kylee L. Martens, MD, of Oregon Health & Science University, and Jason A. Freed, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both coauthored the Iron Consortium guideline.
Dr. Martens emphasized that ferritin is the most useful noninvasive marker of iron deficiency but noted that lower diagnostic thresholds may miss patients who could benefit from iron repletion. She also argued that traditional sex-specific hemoglobin thresholds may contribute to underrecognition of iron deficiency in menstruating patients.
Dr. Freed emphasized moving away from binary ferritin thresholds and instead using a Bayesian approach that considers pretest probability, symptoms, medical history, transferrin saturation, mean corpuscular volume, hemoglobin trends, and likelihood of benefit from iron repletion.
The physicians differed most clearly on gastrointestinal evaluation. The American Gastroenterological Association suggests bidirectional endoscopy in asymptomatic premenopausal women with iron deficiency anemia when no other unequivocal cause is identified, but the recommendation is conditional and based on limited evidence.
Dr. Martens said she would maintain a low threshold for bidirectional endoscopy when the cause of iron deficiency is uncertain, citing the difficulty of accurately quantifying menstrual blood loss and the rising incidence of colorectal cancer among younger adults. She also noted that endoscopy may identify clinically relevant lesions beyond cancer.
Dr. Freed favored a more selective approach in most asymptomatic premenopausal patients with heavy menstrual bleeding. He noted that in women aged 20 to 49 years with iron deficiency anemia, gastric cancer was found in 0.06% and colon cancer in 0.27%, rates 30 to 40 times lower than those reported in men and postmenopausal women. He also argued that the American Gastroenterological Association recommendation may overestimate cancer risk in this population because it relied on observational studies that included patients with gastrointestinal symptoms.
Dr. Freed recommended gynecologic evaluation, serologic testing for celiac disease, and iron repletion before endoscopy in most asymptomatic premenopausal patients with heavy menstrual bleeding. He favored endoscopy if patients had gastrointestinal symptoms, a family history of colon cancer, recurrent iron deficiency despite treatment and management of heavy menstrual bleeding, or unclear menstrual blood loss.
The physicians also differed on initial iron replacement. Dr. Martens supported earlier use of intravenous iron in patients with ongoing blood loss, including heavy menstrual bleeding, particularly when oral iron may not keep pace with iron losses or when rapid repletion is needed. She cited evidence from postpartum anemia and iron-deficient blood donor populations showing greater ferritin or hemoglobin responses with intravenous iron compared with oral therapy, but this evidence was not specific to premenopausal patients with heavy menstrual bleeding. She also noted that anaphylaxis with modern intravenous iron formulations is rare.
Dr. Freed recommended oral iron first for most patients without impaired absorption or an urgent need for rapid repletion. His preferred regimen was ferrous sulfate 325 mg nightly, with repeat laboratory testing after 4 to 6 weeks. If hemoglobin does not increase by at least 1 g/dL, he said physicians should consider whether iron deficiency is not the primary cause or whether oral iron is ineffective because of absorption issues, intolerance, or ongoing blood loss.
The discussion also addressed several practical questions in an appendix. The physicians distinguished complement-activation-related pseudoallergy reactions to intravenous iron from IgE-mediated hypersensitivity reactions such as anaphylaxis, and noted that pica or pagophagia may support a diagnosis of iron deficiency when present. They also questioned routine every-other-day iron dosing as a first-line strategy; Dr. Freed argued that the trial frequently cited to support it dosed its daily-iron arm for only half the study period, which he said does not reflect real-world use.
Because the article was a Grand Rounds discussion rather than an original clinical trial, it did not provide new outcomes data. Instead, it illustrated how expert interpretation may differ when guidelines address overlapping but not identical clinical questions.
In the patient video accompanying the article, Ms. B reported taking oral iron for about 1 year without the laboratory improvement her hematologist expected. Her hematologist subsequently recommended intravenous iron, although she had not yet received the infusion because of a scheduling conflict.
Disclosures: All relevant financial relationships were mitigated. Disclosure forms were available with the article online.
Source: Annals of Internal Medicine
