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Misleading label creates yet another barrier for IV iron use in pregnancy

In 2021, the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) announced that there would be a new adverse event label on the use of intravenous (IV) iron in pregnancy. The adverse event list would now include risk of fetal bradycardia and fetal demise in the event of severe maternal hypersensitivity or anaphylaxis to IV iron.

When Jennifer Teichman, hematology fellow at the University of Toronto, heard about this, she worried that this would make it harder for pregnant patients to access IV iron infusions. For Teichman, iron deficiency in pregnancy was an academic interest that later became deeply personal.

Iron deficiency and iron deficiency anemia are extremely common conditions during pregnancy but are often overlooked. Maternal anemia is associated with numerous poor health outcomes. For the pregnant patient, these adverse outcomes include unplanned C-sections, preterm delivery, peripartum red blood cell transfusions, and maternal death. For the baby, maternal anemia has been linked with low birth weights, low APGAR scores and even long-term neurodevelopmental disorders including autism spectrum disorder and attention deficit hyperactivity disorder.

The good news is iron deficiency is completely correctable with iron supplementation, whether oral or IV. Oral iron is often tried first, but many patients experience significant gastrointestinal side effects that cause them to discontinue treatment. In pregnancy, some of these side effects may be even worse. For some, oral iron just isn’t enough to replete iron stores fast enough. As anemia becomes more prevalent and severe in later trimesters, IV iron is used to quickly and safely increase patients’ hemoglobin and iron stores. It is better tolerated overall and when compared to oral iron does not have higher risk of serious adverse effects.

Teichman’s research found that in Ontario, despite being a high-resource setting with a publicly funded health-services system, more than half of pregnancies were complicated by iron deficiency and more than 40 per cent of pregnant patients were never screened with a simple blood test. She also found that patients of lower socio-economic status are less likely to be screened.

During Teichman’s own pregnancy, she experienced first-hand the challenges of getting tested and treated for iron deficiency anemia. She requested a ferritin check, which screens for iron deficiency, as this test isn’t included in standard prenatal testing in Ontario. When her ferritin came back low, she took iron pills that caused nausea and stomach upset. However, she managed to continue taking the pills and made it through pregnancy without developing anemia.

Then, one month after delivering her son, she had a delayed postpartum hemorrhage and was admitted to hospital. “I had to get a blood transfusion, which was exactly what I had been trying to avoid,” Teichman says. Red blood cell transfusions, although lifesaving in the emergency setting, are associated with much greater risks than IV iron.

She was discharged from hospital still profoundly anemic and received outpatient IV iron infusions.

“I had a completely new and deep appreciation for anemia and what our anemic patients experience; it’s exertional shortness of breath when climbing the stairs or trying to take care of your one-month-old. It’s pounding headaches and complete exhaustion…,” she says. “Within a week of the first (IV iron) infusion, I felt remarkably better. Within a month, I was back to the exercise routine I’d been doing prior to delivery.”

Although IV iron during her pregnancy could not have prevented her postpartum hemorrhage, it may have prevented the need for a blood transfusion and post-partum IV iron helped her avoid a second blood transfusion. She notes that for patients who are not able to receive blood transfusions, for example due to religious reasons, IV iron can be lifesaving.

Nicola Goldberg, also a hematology fellow in Toronto, ran into similar challenges during her pregnancies. During her first pregnancy, her bloodwork showed that she had anemia. Even though iron deficiency is the most common cause of anemia, she had to specifically request to have her ferritin checked. Her OB care provider then started her on iron pills, but these gave her intolerable GI side-effects. In the end, Goldberg contacted one of her hematology supervisors, who immediately arranged for IV iron infusions.

“By my second trimester, I was tired all the time. I felt so slow at work and tasks that came easily to me before were so hard,” says Goldberg. “Within weeks of my final IV iron infusion, I felt like a completely different person – like my pre-pregnancy self. Before, I thought feeling terrible was just what pregnancy was supposed to be like. People commented that I had looked so pale and seemed much better after.”

Both women ran into barriers getting diagnosed with iron deficiency and accessing treatment with IV iron. Goldberg is concerned about other patients, almost all of whom will not be as knowledgeable or privileged. “If this can happen to me, a doctor who’s specializing in hematology, and I didn’t know how to manage (iron deficiency) during my pregnancy, how can you expect anyone else to know?”

Iron deficiency in pregnancy is already underdiagnosed and undertreated. Ultimately, the FDA and EMA’s adverse event label may lead to more barriers for patients in accessing important, timely treatment.

In our experience, the risk of fetal bradycardia or fetal demise pertains to a theoretical risk of fetal harm in the event of maternal anaphylaxis. The current labelling is misleading for both clinicians and patients. We therefore call upon the FDA and EMA to change their adverse event labelling to more accurately reflect the risks of maternal IV iron administration, for example, “as with intravenous formulations of any drug infusion, severe maternal hypersensitivity reactions may occur which could lead to fetal harm.”

Many health-care providers have signed our petition to call for a change in current labelling. Please consider adding your name to help fight the insidious health inequity of iron deficiency in pregnancy.

Sign our petition here.

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3 Comments
  • Michael Auerbach says:

    One of the most dangerous issues with FDA is their perception that they are knowledgeable about the topic. I actually had a conference call with them. They made up the reason that “IV iron is associated with anaphylaxis which can cause fetal demise”. When I asked them if penicillin had a similar label they responded with “that’s not our issue”. Being ignorant of a topic is one issue, but being ignorant and perseverating that you are not is dangerous. The FDAs handling of intravenous iron has done tremendous harm in the last three decades. Dexferrum which terrorized Canadian physicians is one example and now a premature approval of a generic for ferumoxytol which clearly looks to be less safe. FDA is in serious need of an expert on IV for the hematology drug approval committee because of this writing it is quite clear that such an individual is absent.

  • Helen Aqua says:

    Iron deficiency during pregnancy can be also a symptom flagging celiac disease. Treating it as ‘common’ pregnancy caused anemia without consideration of this alternate root cause delays a celiac disease diagnosis. If it is indeed a celiac reaction to stress—the stress being the pregnancy—future anemia episodes can be anticipated in future pregnancies and addition oral iron will correct.

  • Ann Montgomery says:

    Midwife, Nunavik Régional Health
    PhD Epidemiology

Authors

Sophia Wen

Contributor

Sophia Wen is an internal medicine resident at the University of Toronto.

Michelle Sholzberg

Contributor

Michelle Sholzberg is the head of the division of Hematology-Oncology at St. Michael’s Hospital. Her clinical and research focus is on common anemias, hemostasis and health equity. She has received unrestricted research and educational support from Pfizer.

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