How Should We Treat Pregnant Women With Iron Deficiency?

Iron deficiency is prevalent among pregnant women, as maternal iron is used to supply the needs of the fetus and placenta, and additional iron is required to replace iron lost due to bleeding at delivery. This condition is associated with increased risks for adverse outcomes for the mother and baby, like preterm birth and low birth weight. Standard treatment of iron deficiency and iron-deficiency anemia relies on iron supplementation, but questions remain about the optimal delivery route.

There are five intravenous (IV) iron products available in the U.S., but few clinical-trials data to guide their use in pregnant women with iron deficiency. Here, ASH Clinical News invited Michael Auerbach, MD, and Ralph V. Boccia, MD, to discuss the optimal approach for delivering IV iron in pregnant women with iron deficiency. Dr. Auerbach is a practicing hematologist at Auerbach Hematology and Oncology in Baltimore and a clinical professor of medicine at Georgetown University School of Medicine in Washington, DC. Dr. Boccia is a clinical associate professor of medicine at Georgetown University School of Medicine in Washington, DC, and founder and medical director of the Center for Cancer and Blood Disorder in Maryland.

Michael Auerbach, MD: In the U.S., the standard treatment for pregnant women with is oral iron, administered daily as two to three 325-mg tablets containing approximately 50 to 65 mg elemental iron.¹ While oral iron is inexpensive and readily available, more than 70 percent of women experience significant gastrointestinal symptoms, including metallic taste, gastric irritation, and worsening of constipation that is already present due to high progesterone levels; for pregnant women who already experience other gastrointestinal symptoms, this is a heavy burden.

Oral iron also may be an inadequate treatment for pregnant women with iron deficiency, as shown in recent studies suggesting that, if a mother’s ferritin level is <15 μg/mL, the iron status of the neonate is compromised.²

In a prospective trial of 2,400 pregnant women with iron deficiency who received oral iron, maternal hemoglobin (Hb) and iron parameters improved, but 45 percent of the neonates were iron-deficient at birth. This wouldn’t be a big deal, except that neonatal iron deficiency has been associated with statistically significant increase in cognitive and behavioral abnormalities that persist through early adulthood.³

IV iron – in any of its preparations – is underused in this setting.

Ralph V. Boccia, MD: I agree, and I would add that oral iron probably is overused in the general population – not just in pregnant women. Still, oral iron in the pregnant population presents many problems, as these women already have fatigue, have a lower exercise tolerance, and tend to become more anemic during pregnancy. Because of these factors, pregnant women are also less likely to remain adherent or compliant with oral iron.

Parenteral iron is a good option for patients with iron deficiency, and particularly for pregnant women who have impaired iron absorption. Given the data about neonatal concerns, why wouldn’t we want to be treating these patients with IV iron?

Dr. Auerbach: We agree completely on that point. The issue, then, is which iron should we use? Six formulations are available in the U.S. and Europe: ferric gluconate (FG), iron sucrose (IS), low-molecular-weight iron dextran (LMWID), ferric carboxymaltose (FCM), iron isomaltoside, and ferumoxytol. Based on the preponderance of data from prospective trials, they are all equally safe and efficacious.

For the sake of this discussion, I believe we can discard two options right away: FG and IS. These agents are administered over five visits, while other iron products require only one visit to achieve the same effect. So, while FG and IS are safe and effective, we can’t reasonably expect a pregnant woman to come into the clinic for five or more visits for IV iron.

The remaining options (LMWID, FCM, iron isomaltoside, and ferumoxytol) are all excellent formulations, but each requires different dosing and administration.

Although it is an off-label usage, LMWID is routinely administered at 1,000 mg for one hour in pregnant women with iron deficiency. We have little evidence about ferumoxytol in the pregnant population, but, anecdotally, we have treated several hundred patients with ferumoxytol 1,020 mg administered in a 15-minute infusion. However, this is not routinely approved and then we routinely give ferumoxytol 510 mg on two different days in three to five minutes because we know it to be safe. The drug was originally approved at a rapid infusion rate (510 mg over 17 seconds), but the 15-minute infusion time was adopted after a high rate of infusion reactions was observed.⁴ Personally, I think that the 15-minute approval was an overreaction to the earlier imprudent use of that drug. This formulation cost 400 percent of the price of LMWID.

FCM is another excellent iron product. It can be given as a single 1,000-mg infusion in 15 minutes. There is a litany of evidence to support this dosing, but, in the U.S., FCM is only available as a 750-mg vial. Because published evidence suggests giving more than 1,000 mg at once is not clinically beneficial, we are forced to use 1,500 mg of this drug to give a 1,000-mg dose. Therefore, as the per-mg price of FCM is the highest of the four formulations, administering FCM costs 600 percent more than administering LMWID and 150 percent of the cost of ferumoxytol.

Dr. Boccia: We have used all three of these iron products and our experience with them in the pregnant population has been equally good. With FCM, the question will always be, “How much should we give – 1,000 mg or 1,500 mg?”

In the “old days,” we would calculate the dose deficit, based on the amount of iron the patient needed (accounting for body size and Hb levels). For example, a woman presenting with a Hb 7 g/dL and iron deficiency is clearly going to need more iron than a woman who has a Hb 11.5 g/dL and is iron deficient but only mildly anemic. In all likelihood, the first patient would do better with a 1,500-mg dose, while the second patient would benefit from a 1,000-mg dose.

Dr. Auerbach: You’re right – a 1,500-mg dose probably is more prudent in someone with lower Hb levels. The question is, “Should you give her 1,500 mg in one treatment, or should you divide it, wait four weeks, and then give the second part of the treatment?” That statement is supported by prospective data, and it means we are wasting a lot of money by using a drug available only in a 750-mg vial.

If we had the luxury of having the European vial sizes of 500 mg and 1,000 mg available in the U.S., then this entire argument goes away. In the U.S., a 750-mg vial of FCM costs $538; in the U.K., a 1,000-mg vial costs approximately $156. So, other high-resource countries are paying a fraction of what U.S. clinicians are paying for the same drug.

I don’t understand why, in the U.S., we are stuck with a 750-mg vial of FCM. We are wasting a lot of money by using a drug available only in a 750-mg vial, which costs $538, versus giving a 1,000-mg dose of LMWID in one sitting, which will cost $240.

Dr. Boccia: FCM is a great, safe option, and it is nice to be able to administer an iron therapy in 15 minutes. At times, I use one vial of FCM, rather than using a second vial to deliver 750 mg. Also, in lighter-weight patients, I will administer 500 mg of a 750-mg vial; then, if the patient appears to have an iron deficit lower than 1,500 mg, I will give them one 750-mg dose and monitor their response over time.

Dr. Auerbach: That’s a prudent clinical paradigm, and one that we have to consider because of the pricing. I might argue for the use of FCM in iron-deficient pregnant women, but, because of the costs, I think we have to explore other options for administering IV iron.

The trial also suggested that we are not able to use more than 1,000 mg in a short period of time. That is consistent with in vitro data. Unfortunately, we don’t know what happens to IV iron after administration because we haven’t had any in vitro data to answer these questions.

Dr. Boccia: At this time, research shows that we can correct a patient’s anemia to a similar degree with different IV iron formulations, but it doesn’t tell us whether the patient’s underlying iron deficiency can be corrected better with one form of IV iron over another or one dose over another, and – importantly – if one dose might result in a more durable correction in that population of patients with repeated need.

Dr. Auerbach: In the FIRM study, when we monitored Hb and transferrin levels five weeks from baseline and there was no difference between patients treated with FCM or ferumoxytol.

Dr. Boccia: And that is only at five weeks. To answer the clinically important questions that would guide our therapy choice in this population, we also need trials with longer follow-up. The cutoff for follow-up in these studies ranges from 35 to 50 days.

If we measure the levels at a fairly short interval, are those numbers going to be reflective of true iron stores? Or, has the iron restoration not completely occurred yet? I would like to have data through six months of follow-up to see when patients required retreatment with iron. Without those data, all we can do is speculate about the differences between doses.

Dr. Auerbach: That’s an extremely important question, but, unfortunately, I’m not sure that we are going to get those data. I can’t recall anything in the existing literature to support or refute that claim.

I think our only disagreement about the optimal method of administering IV iron is whether this huge cost differential is a compelling argument to use one formulation over another. Outside of the U.S., I imagine that we would both agree that pregnant women in the second and third trimester who have iron deficiency or iron-deficiency anemia should receive IV iron and not oral iron – mostly to protect fetal brain growth and development. Future trials that consider cost-effectiveness and duration of response should provide us with more data to guide these decisions.

References

1. Auerbach M. Commentary: Iron deficiency of pregnancy – a new approach involving intravenous iron. Reprod Health. 2018;15(suppl 1):96.
2. Zhao G, Xu G, Zhou M, et al. Prenatal iron supplementation reduces maternal anemia, iron deficiency, and iron deficiency anemia in a randomized clinical trial in rural China, but iron deficiency remains widespread in mothers and neonates. J Nutr. 2015;145:1916-23.
3. Congdon E, Westerlung A, Algarin C, et al. Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. J Peds. 2012;160:1027-3.
4. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warnings and changes prescribing instructions to decrease the risk of serious allergic reactions with anemia drug Feraheme (ferumoxytol). Accessed September 9, 2018, from https://www.fda.gov/Drugs/DrugSafety/ucm440138.htm.
5. Adkinson NF, Strauss WE, Macdougall I, et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: a randomized trial. Am J Hematol. 2018;93:683-90.