We asked, and you answered! Here are the responses from this month’s “You Make the Call” question on how you would treat borderline anemic pregnant patients.
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All pregnant patients in their second and third trimester who have ferritin levels below 30 µg/L should receive iron infusions, regardless of their hemoglobin levels. This is a public health issue affecting unborn children.
Steven Fein, MD, MPH
Miami, FL
I would certainly start these patients on oral ferrous sulfate, at least 65 mg per day. Iron transfer to the fetus occurs during the last trimester, so the sooner, the better. In view of the frequency of doctor visits required of a pregnant patient and the expense, I would not start with IV iron. However, if oral iron fails after a month, then IV iron may be reasonable.
Susumu Inoue, MD
Flint, MI
I believe there is enough evidence of increased adverse pregnancy outcomes in this setting. It is very important to ensure babies are born without iron deficiency. Oral iron could be used initially; however, I would recommend IV iron after the first trimester.
Eduardo Reynoso, MD
Mexico City, Mexico
I would treat these patients with IV iron such as iron sucrose.
Samir Desai, MD
Utica, NY
I would definitely treat pregnant patients with IV iron. I would check iron studies even if there is no anemia in the second trimester. Pregnancy by itself is exhausting, and iron deficiency makes it worse. Additionally, postpartum women need energy to take care of a newborn. I can personally vouch for this. My hemoglobin levels were normal during pregnancy, but my ferritin was less than 50 µg/L and transferrin saturation (TSAT) was less than 20%. Getting IV iron in the second trimester resolved my fatigue completely.
There are studies that show an increased risk of autism in children if the mother was iron deficient during pregnancy, and there is an increased risk of neurocognitive dysfunction in neonates. I don’t like to use oral iron in pregnancy except in the first trimester because it takes a long time to work and worsens constipation. IV iron is safe starting in the second trimester, so I always advocate for checking ferritin, TSAT, and total iron binding capacity (TIBC) in all pregnant patients irrespective of anemia. I would give IV iron even if ferritin levels are normal (more than 50 or 100 µg/L), if TSAT is low (less than 20%), and TIBC is high (more than 400 µg/L).
Yazhini Vallatharasu, MD
Appleton, WI
Yes, these patients should be supplemented [with iron].
Bruce Raphael, MD
New York, NY
For anemia during pregnancy, I first confirm there is correctable cause of iron deficiency.
Usually, the patients already take an oral iron tablet supplement (e.g., ferrous sulfate 200 mg/day). Provided that compliance is not an issue, I would give a high dose or oral replacement (e.g., 200 mg/three times daily). The alternative daily oral iron should not affect hemoglobin levels. Hemoglobin response is slow, so I would follow it throughout the next month. In my experience, the success rate is 80% to 90%, but in some cases, hemoglobin only improves to the borderline of that gestational age. I follow ferritin only in cases that failed to have hemoglobin response to see if iron deficiency anemia is still the cause.
If oral therapy fails or results in intolerance, I use IV iron. I use either iron sucrose or iron carboxymaltose depending on affordability. I'm lacking data on pregnancy outcomes and long-term development outcome of the babies following this regimen.
Kaipol Takpradit, MD
Bangkok, Thailand
My approach would be to try to clearly differentiate true iron deficiency anemia from a normal pregnancy with a low ferritin. My reasons for doing so relate to the conflicting data regarding the risk-to-benefit ratio of routine iron replacement in pregnancy and the problem of treating the numbers. I accept that pharma-sponsored trials have suggested a benefit of treating “subclinical” iron deficiency in pregnant patients, but this must be balanced by the observational data suggesting a potential prognostic benefit with mild “anemia” in pregnancy. I do not believe that we have a robust data set to know what level of ferritin should be treated with iron supplement in an otherwise normal pregnancy. I am also concerned with what the ferritin surge, and subsequent drop, after an iron infusion means physiologically. There is certainly evidence that iron withholding is an important physiologic mechanism to protect from infection in the setting of the immune tolerance of pregnancy. Changes in ferritin are driven by many factors, including the increase with inflammatory stimuli. We know that elevated ferritin is an independent poor prognostic in certain situations, such as ICU admission.
Until these issues are resolved, my own approach is to always try to diagnose the cause of anemia before deciding treatment. Accepting interpretation of iron studies, especially serum ferritin, is complex, and it is dangerous to try to apply simple algorithmic rules. I am also of the opinion that treating a number (that we do not well understand) in an otherwise healthy pregnant patient is against the important principle of primum non nocere.
John Hounsell, MD
Warrnambool, Australia
There has been a lot of discussion surrounding appropriate diagnostic criteria for iron deficiency (with and without anemia). Much of this discussion was catalyzed by recent basic and clinical studies attempting to define diagnostic criteria based on hematologic responses to iron deficiency, such as increases in the soluble transferrin receptor (TfR). The discussion was beautifully summed up in the article “Sex, Lies, and Iron Deficiency: A Call to Change Ferritin Reference Ranges” by Kylee Martens, MD, and Thomas G. DeLoughery, MD, MACP.1
Certainly, iron deficiency anemia during pregnancy is associated with adverse maternal and fetal outcomes. Even in the absence of anemia, iron deficiency during pregnancy is associated with low birth weight, prematurity, intrauterine growth restriction, and other risks and leads to postnatal iron deficiency in the neonate, which has been linked to short-term and long-term risks to neurodevelopment.2 Non-anemic iron deficiency is also associated with fatigue, cognitive deficits, sleep issues, and decreased aerobic capacity, which compound symptoms affecting quality of life and function during pregnancy. Finally, it is important to consider that reference ferritin levels are derived from the range describing 95% of the population, which includes a large proportion of premenopausal female patients with depleted iron stores due to chronic blood loss from menstruation. An example of a typical reference range for ferritin is 16 to 154 μg/L for female patients ages 16 to 40 years, a range that is not necessarily prescriptive of “normal” iron levels.
What, then, would be an appropriate lower limit of the ferritin range that describes adequate iron stores? This represents an active area of debate, and there is currently no universal consensus, with some utilizing a lower cutoff of more than 30 μg/L, while others propose a target of more than 50 μg/L or even more than 100 μg/L. We consider that iron acquisition is upregulated in response to iron deficiency, with one mechanism being upregulation of TfR expression.3 Stable isotope studies using oral iron-57, iron-58, or iron-54 to track iron uptake4 or soluble TfR levels5 indicate that the approximate ferritin level at which the body ceases to upregulate iron uptake in response to iron deficiency is at or above 50 μg/L. Thus, to avoid negative iron balance in pregnancy, iron supplementation to ferritin levels greater than 50 μg/L would be necessary. This provides a physiologic justification for treating pregnant patients with oral or intravenous iron to increase ferritin levels to at least 30 μg/L.
Yvette Yien, PhD
Pittsburgh, Pennsylvania
Julia Xu, MD
Pittsburg, Pennsylvania
References:
- Martens K, DeLoughery T. Sex, lies, and iron deficiency: a call to change ferritin reference ranges. Hematology Am Soc Hematol Educ Program; 2023;1:617-621.
- Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol. 2020;223(4):516-524.
- Anderson CP, Shen M, Eisenstein RS, et al. Mammalian iron metabolism and its control by iron regulatory proteins. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2012;1823(9):1468-1483.
- Galetti V, Stoffel NU, Sieber C, et al. Threshold ferritin and hepcidin concentrations indicating early iron deficiency in young women based on upregulation of iron absorption. EClinicalMedicine. 2021;39(101052).
- Tarancon-Diez L, Genebat M, Roman-Enry M, et al. Threshold ferritin concentrations reflecting early iron deficiency based on hepcidin and soluble transferrin receptor serum levels in patients with absolute iron deficiency. Nutrients. 2022;14(22):4739.