Arielle Langer, MD, MPH
Director, Women’s Bleeding and Clotting Disorders Program
Brigham and Women’s Hospital
CLINICAL DILEMMA
My hematology colleagues and I are being referred pregnant patients with borderline microcytic or normocytic anemia and ferritin levels of less than 10 µg/L. Obstetrics literature suggests that we treat these patients with oral or intravenous (IV) iron to increase ferritin levels to greater than 30 µg/L. Is there a hematologic justification for this recommendation?
EXPERT OPINION
A recommended minimum ferritin of 30 µg/L in pregnant patients is based on several considerations: inherent problems with common ferritin reference ranges, challenges in the interpretation of mean corpuscular volume (MCV), maternal health concerns, and fetal outcomes.
Ferritin reference ranges have historically been defined by a normal distribution, which necessarily mislabels some patients with iron deficiency as being iron replete. Specifically, the use of a 95% confidence interval as the reference range inherently includes patients with iron deficiency, given that 9% to 39% of all women are iron deficient.1–4 Several studies, as well as a multidisciplinary consensus statement and Hematology, ASH© Education Program, support a lower ferritin reference limit of 30 µg/L or 50 µg/L to more accurately define iron deficiency.5–11 These are the thresholds relevant to intervention in pregnancy.
Because not all patients with iron deficiency have anemia, this clinical dilemma highlights another important consideration: Should normocytic anemia be attributed to iron stores in pregnancy? Given the life span of red blood cells, MCV takes weeks to shift noticeably. These kinetics are not specific to pregnancy but reflect the limitation of using MCV in any acute iron deficiency, and this limitation is more pronounced the more rapid the onset. Additionally, frank iron deficiency has been shown to occur in pregnancy with a normal or even elevated MCV.12 We know that in liver disease there is diminished correlation between MCV and iron stores because of alterations of membrane composition.13 Whether due to a similar phenomenon in pregnancy, a different mechanism altogether, or simply the rapidity of onset, MCV is not a sensitive screening tool to detect iron deficiency in pregnancy.
Iron deficiency doesn’t feel good, and many of its symptoms may also be misattributed to normal pregnancy. While symptoms from pregnancy are often unavoidable, this should not justify forgoing intervention that can make a pregnant person feel better. Additionally, a systematic review of studies of routine iron supplementation without selecting for iron deficiency showed that it results in less anemia.14 While we don’t have randomized data on iron administration in patients with confirmed iron deficiency that quantify how much transfusion is avoided or how much better patients feel, we don’t need those data any more than we need a randomized trial proving the efficacy of penicillin.
While maternal health is sufficient to justify intervention, we would be remiss to ignore the growing body of literature about the effects of iron deficiency on fetal health as well. Though not all neurodevelopmental studies have found impacts,15 in utero iron deficiency has been associated with modestly lower neurocognitive metrics in infants and children up to age 10.16–18 Some studies have also shown that iron deficiency or anemia increase rates of perinatal and neonatal mortality, low birth weight, and preterm birth.14,19,20 The variable results may reflect the wide spectrum of severity of both anemia and iron deficiency.
When considering route of administration, not all patients will need IV iron, and a trial of oral iron is usually appropriate. This trial should be limited in length, however, to assure that there is still time for IV administration if oral iron is ineffective. Firstline treatment with IV iron can be considered in patients with prior bariatric surgery, severe anemia, prior intolerance of oral iron, or severe constipation. Importantly, all formulations of IV iron are safe in pregnancy.21,22
In summary, an absolute minimum ferritin of 30 µg/L is an appropriate goal for pregnant patients, and levels falling below this threshold merit treatment, including the use of IV iron when oral administration is insufficient.
References
- Siu AL, U.S. Preventive Services Task Force. Screening for iron deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;163(7):529-536.
- Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Am J Clin Nutr. 2011;93(6):1312-1320.
- Weyand AC, Chaitoff A, Freed GL, et al. Prevalence of iron deficiency and iron-deficiency anemia in US Females Aged 12-21 Years, 2003-2020. JAMA. 2023;329(24):2191-2193.
- Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):973976.
- Parker ML, Storm S, Sholzberg M, et al. Revising ferritin lower limits: it’s time to raise the bar on iron deficiency. J Appl Lab Med. 2021;6(3):765-773.
- Naveed K, Goldberg N, Shore E, et al. Defining ferritin clinical decision limits to improve diagnosis and treatment of iron deficiency: A modified Delphi study. Int J Lab Hematol. 2023;45(3):377-386.
- Ning S, Zeller MP. Management of iron deficiency. Hematology Am Soc Hematol Educ Program. 2019;2019(1):315-322.
- Martens K, DeLoughery TG. Sex, lies, and iron deficiency: a call to change ferritin reference ranges. Hematology Am Soc Hematol Educ Program. 2023;2023(1):617-621.
- Vaucher P, Druais P-L, Waldvogel S, et al. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012;184(11):1247-1254.
- Peyrin-Biroulet L, Williet N, Cacoub P. Guidelines on the diagnosis and treatment of iron deficiency across indications: a systematic review. Am J Clin Nutr. 2015;102(6):1585-1594.
- Koulaouzidis A, Cottier R, Bhat S, et al. A ferritin level >50 μg/L is frequently consistent with iron deficiency. European Journal of Internal Medicine. 2009;20(2):168-170.
- Santana G, Reise R, Koenig M, et al. Evaluating test utilization for anemia during pregnancy. Int J Lab Hematol. 2022;44(3):673-678.
- Gkamprela E, Deutsch M, Pectasides D. Iron deficiency anemia in chronic liver disease: etiopathogenesis, diagnosis and treatment. Ann Gastroenterol. 2017;30(4):405-413.
- Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, et al. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;(7):CD004736.
- Iglesias L, Canals J, Arija V. Effects of prenatal iron status on child neurodevelopment and behavior: A systematic review. Crit Rev Food Sci Nutr. 2018;58(10):1604-1614.
- Geng F, Mai X, Zhan J, et al. Impact of fetal-neonatal iron deficiency on recognition memory at 2 months of age. J Pediatr. 2015;167(6):1226-1232.
- Congdon EL, Westerlund A, Algarin CR, et al. Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. J Pediatr. 2012;160(6):1027-1033.
- Janbek J, Sarki M, Specht IO, et al. A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment. Eur J Clin Nutr. 2019;73(12):1561-1578.
- Jung J, Rahman MM, Rahman MS, et al. Effects of hemoglobin levels during pregnancy on adverse maternal and infant outcomes: a systematic review and meta-analysis. Ann N Y Acad Sci. 2019;1450(1):69-82.
- Rahman MM, Abe SK, Rahman MS, et al. Maternal anemia and risk of adverse birth and health outcomes in low-and middle-income countries: systematic review and meta-analysis. Am J Clin Nutr. 2016;103(2):495-504.
- Gerb J, Strauss W, Derman R, et al. Ferumoxytol for the treatment of iron deficiency and iron-deficiency anemia of pregnancy. Ther Adv Hematol. 2021;12. doi: 10.1177/20406207211018042 .
- Achebe MM, Gafter-Gvili A. How I treat anemia in pregnancy: iron, cobalamin, and folate. Blood. 2017;129(8):940-949.
NEXT MONTH'S CLINICAL DILEMMA
A 46-year-old female patient was diagnosed with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (B-ALL) after presenting with leukocytosis, lymphadenopathy, and hepato-splenomegaly. A bone marrow biopsy showed hypercellularity (>90%), and flow cytometry analysis showed 36% B-cell lymphoblasts. Cytogenetics were abnormal with hyperdiploidy karyotype; gain of 2, 5, and 8; t(9;22); del 11q; and +der(22). Fluorescence in situ hybridization showed t(9;22) and detected KMT2A.
In total, she received seven cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus ponatinib (four odd — or “A” — cycles and three even — or “B” — cycles); the last cycle was omitted because of excessive toxicity. She was in complete remission (CR) and negative for measurable residual disease after her first two cycles. She also received intrathecal (IT) prophylaxis with 15 alternating cycles of methotrexate (MTX) and cytarabine.
She was not a candidate for an allogeneic hematopoietic cell transplant because of social issues. Therefore, over the next two years she received POMP (prednisone, oncovin, melphalan, and cyclophosphamide) and ponatinib as maintenance, but treatment was often interrupted and then discontinued because of intolerability and frequent infections. Her ponatinib was also switched to dasatinib because of increased liver enzymes and abdominal pain. During the two years of maintenance treatment after CR, her polymerase chain reaction (PCR) test results remained negative.
The patient has a history of Arnold Chiari malformation, which had been under observation. She was admitted with headaches and noted to have hydrocephalus, likely from Arnold Chiari malformation; however, cerebrospinal fluid (CSF) cytology was also positive for B-ALL. Her bone marrow showed no morphologic evidence of leukemia, and flow cytometry was negative, but PCR for BCR-ABL was 0.8% positive. She was treated for hydrocephalus with a ventriculoperitoneal (VP) shunt. She also received IT chemotherapy plus one cycle of high-dose MTX with clearing of CSF. Later, she was readmitted with headaches. At that time, she had a VP shunt, malposition, and an infected ommaya reservoir. The ommaya reservoir was removed, and the VP shunt was replaced. CSF cytology remains negative, and peripheral blood PCR remains negative for any transcript.
What do you recommend as future treatment for this patient? Some have advised chimeric antigen receptor T-cell therapy, but the current plan is one more cycle of high-dose MTX followed by blinotumumab.
How would you respond? Email us at [email protected].
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