Morbidity and mortality in 128 otherwise healthy Canadian children with severe iron deficiency anemia in the setting of ongoing bottle use and excessive cow's milk intake: A massive preventable problem demanding action

Abstract Introduction: Iron deficiency (ID) is the most common nutritional deficiency in the world, and an estimated 10% of American and Canadian children <5 years old suffer from ID anemia (IDA). In many parts of the world, the incidence of IDA is much higher. As iron is required by virtually all cells in the body, ID/IDA can lead to many physiological complications, including impaired neurodevelopment (which may persist even after iron supplementation), poor growth, decreased immune function, heart failure, stroke, and even death. Term infants usually have enough iron (obtained in-utero) for the first 4-6 months of life and must then must consume adequate dietary iron to maintain their stores. Excessive cow’s milk intake, often from ongoing bottle use after 1 year of age, is a leading cause of IDA. In addition to reducing the child’s appetite for solid foods, excessive cow’s milk consumption damages the gastrointestinal mucosa, which can lead to microvascular blood loss and protein-losing enteropathy. We sought to describe the burden of severe IDA, associated complications, interventions needed, and to identify risk factors for IDA in this patient population. Methods: We performed a 5-year retrospective case review of 128 children seen at the Hospital for Sick Children in Toronto, Canada, from January 2020 to December 2024. Included were patients aged 0-5 years with severe anemia (hemoglobin (Hb) ≤5.0 g/dL and MCV ≤70 fL) and ≥1 marker of ID (ferritin <15 ng/mL, transferrin saturation <20%, soluble transferrin receptor >1.9 mg/L, reticulocyte hemoglobin equivalent <21.55 pg). Patients were excluded if they had any concurrent chronic illness (e.g. kidney disease, inflammatory bowel disease, congenital heart disease), an underlying hematologic condition that could independently contribute to anemia (e.g. hemoglobinopathies or thalassemias), an oncology diagnosis, or if they were post-marrow/organ transplant. Our population therefore consisted of otherwise healthy children whose only major health problem was severe IDA. Results: The median Hb at presentation was 3.8 g/dL (1.2-5.0 g/dL). The median age was 23 months (8-55 months); 13% were born premature (9% born at 34-36 weeks and 4% born <34 weeks gestational age). When considering total daily consumption of homogenized cow’s milk, soymilk, or exclusive breastfeeding in children >6 months of age, 90% of children consumed excessive milk; 89% drank >500 mL/day of cow’s milk and 56% drank >1 L/day. Of the patients who were >15 months old, 93% still used a bottle with a nipple. Most patients (n=73; 57%) were hospitalized; Sixty-one patients (48%) received ≥1 red blood cell transfusion, and 27 (21%) received ≥1 intravenous iron infusion. Thirty-nine (31%) children were noted to have development delay. Thirteen children had echocardiograms performed due to concerns with heart function, of which 11 (85%) were abnormal: 5 (39%) had pericardial effusion, 6 (46%) had compensated dilated cardiac chambers, and 3 (23%) had cardiac dysfunction/failure. Four patients had a thrombotic event during their acute presentation: 2 had a cerebral sinus venous thrombosis (CSVT), 1 had a line-related deep vein thrombosis (DVT), and 1 had both a CSVT and a line-related DVT. Two patients died: one aged 27 months from cardiac failure and a CSVT/stroke, and the other aged 22 months from cardiac arrest. Conclusions: Our study demonstrates the tremendous morbidity and mortality that can occur due to severe IDA such as developmental delay, cardiac failure, stroke, and death. Importantly, our review highlights that these complications occur in otherwise completely healthy children, most of whose only risk factor is excessive cow's milk consumption, almost always with the ongoing use of a bottle with a nipple. Our study only captures the most severe cases of IDA in infants and toddlers; the prevalence of less severe cases of IDA is likely to be many fold higher, and this also likely contributes to a lot of morbidity and healthcare resource utilization. As such, this problem is a massive healthcare issue that has not garnered sufficient attention. We wish to educate physicians on the importance of advising families to stop using a bottle with a nipple once a child is 1 year old. We also hope to guide federal policy change for IDA screening and intervention to address this highly preventable medical issue.

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