Overview
Definition:
Late anemia of prematurity (LAP) is a common complication in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants, typically developing after the first few weeks of life (usually beyond 2-4 weeks corrected gestational age), characterized by a progressive decline in hemoglobin levels
It arises from a complex interplay of factors including physiological anemia of infancy, frequent blood sampling for laboratory monitoring, occult blood loss, impaired erythropoiesis, and relative deficiency of erythropoietin (EPO).
Epidemiology:
LAP affects a significant proportion of preterm infants, with incidence rates varying from 40% to 60% in VLBW infants, and even higher in ELBW infants
The severity of prematurity and the amount of blood drawn for investigations are strong determinants of its occurrence and severity
The need for transfusion in the NICU is largely driven by this condition.
Clinical Significance:
LAP can lead to significant morbidity, including impaired neurodevelopment, increased risk of infections, delayed growth, and prolonged hospitalization
Timely and appropriate management is crucial to optimize outcomes for these vulnerable infants and reduce the burden on healthcare resources
Understanding the nuances between ESAs and transfusions is vital for resident-level decision-making.
Etiology And Pathophysiology
Physiological Anemia:
The nadir of hemoglobin concentration in term infants is around 8-10 weeks of life, but in preterm infants, this nadir occurs earlier and at lower levels (typically 5-8 g/dL) due to a higher rate of growth and a proportionally larger blood volume relative to their body weight
The red blood cells in premature infants also have a shorter lifespan.
Impaired Erythropoiesis:
Preterm infants have relatively immature bone marrow, leading to a blunted response to erythropoietin
Iron stores are also limited, especially in preterm infants born to mothers with iron deficiency or who have experienced cord clamping delays
Inflammation and infection can further suppress erythropoiesis.
Blood Sampling And Blood Loss:
Frequent laboratory monitoring in the NICU is a major contributor to blood loss
Significant amounts of blood can be lost through serial blood draws for routine testing (e.g., complete blood counts, electrolytes, blood gas analysis), particularly in critically ill neonates
Occult gastrointestinal blood loss (e.g., from feed intolerance, necrotizing enterocolitis) and iatrogenic blood loss (e.g., from procedures) also contribute.
Erythropoietin Deficiency:
While erythropoietin production increases with gestational age, preterm infants may have a relative or absolute deficiency of EPO, especially in the early weeks of life, leading to inadequate stimulation of erythropoiesis
This is a primary target for ESA therapy.
Clinical Presentation
Symptoms:
Lethargy
Poor feeding or decreased oral intake
Pallor
Tachypnea or increased oxygen requirement
Apnea or bradycardia
Poor weight gain
Jaundice may persist or reoccur
Irritability.
Signs:
Pale conjunctiva and skin
Tachycardia
Tachypnea
Hypotonia
Signs of poor perfusion (e.g., mottled skin, delayed capillary refill)
Reduced activity level
Some infants may be asymptomatic initially.
Diagnostic Criteria:
Diagnosis is primarily based on laboratory findings
A hemoglobin level below a certain threshold, often coupled with a low hematocrit, in a preterm infant with a compatible clinical presentation
The specific threshold for intervention varies by institution and clinical context but generally aims to maintain adequate oxygen-carrying capacity
Common targets for intervention include hemoglobin <7-9 g/dL, with thresholds for transfusion or ESA initiation being higher in infants with cardiopulmonary compromise or significant blood loss.
Diagnostic Approach
History Taking:
Detailed gestational history (gestational age at birth)
Birth weight
Maternal medical history (e.g., anemia, diabetes)
Evidence of antenatal or perinatal complications (e.g., chorioamnionitis, fetal distress)
Clinical course in NICU: feeding tolerance, presence of apnea/bradycardia, oxygen requirements, signs of infection, any evidence of blood loss (melena, hematochezia, vomiting blood)
Details of previous blood transfusions or interventions.
Physical Examination:
Thorough assessment of vital signs (heart rate, respiratory rate, blood pressure, oxygen saturation)
Assessment of hydration status and perfusion
Examination for pallor of mucous membranes and skin
Auscultation of heart and lungs for murmurs or signs of fluid overload/pulmonary compromise
Abdominal examination for distension, tenderness, or signs of gastrointestinal bleeding.
Investigations:
Complete blood count (CBC) with differential and reticulocyte count is essential
Iron studies (serum ferritin, transferrin saturation) are important to assess iron stores, as iron deficiency exacerbates anemia
Blood type and antibody screen if transfusion is being considered
Peripheral blood smear may show microcytosis and hypochromia
Consider tests for occult blood loss (stool guaiac or fecal hemoglobin)
Measurement of erythropoietin levels can be helpful in selected cases but is not routinely performed.
Differential Diagnosis:
Physiological anemia of infancy (general term)
Anemia due to acute blood loss (e.g., trauma, surgery, ruptured omphalocele/gastroschisis)
Hemolytic anemia (e.g., isoimmune, drug-induced, ABO incompatibility)
Vitamin B12 or folate deficiency (rare in premature infants unless maternal deficiency or malabsorption)
Chronic disease anemia
Anemia of chronic inflammation
Congenital dyserythropoietic anemias (very rare)
G6PD deficiency.
Management
General Principles:
The primary goals are to restore adequate oxygen-carrying capacity, prevent symptoms and complications of anemia, and optimize erythropoiesis
Management should be individualized based on the infant's gestational age, postnatal age, clinical status, hemoglobin level, reticulocyte count, and the presence of comorbidities.
Erythropoiesis-stimulating Agents:
ESAs (e.g., recombinant human erythropoietin, epoetin alfa, darbepoetin alfa) are used to stimulate bone marrow production of red blood cells
They are typically initiated when hemoglobin is below a certain threshold (often 8-10 g/dL) and reticulocyte count is low, and in the absence of active infection or significant iron deficiency
A common regimen for epoetin alfa is 50-100 units/kg/day or 150-300 units/kg/week, administered subcutaneously or intravenously, typically for 6-8 weeks
Iron supplementation (intravenous or oral) is crucial concurrently with ESA therapy to provide the necessary substrate for erythropoiesis
Dosing for darbepoetin alfa is less frequent but requires careful monitoring
Side effects are rare but can include hypertension, thrombocytosis, and rarely, seizures.
Red Blood Cell Transfusion:
Transfusion is indicated when hemoglobin levels fall below critical thresholds (often < 7-9 g/dL), or when the infant is symptomatic despite ESA therapy, or experiences significant acute blood loss
Transfusions provide immediate restoration of hemoglobin and oxygen-carrying capacity
The volume of packed red blood cells (PRBCs) transfused is typically 10-20 mL/kg, administered over 2-4 hours
Aims are to raise hemoglobin by 1-2 g/dL per mL/kg
Risks include transfusion reactions (febrile, allergic), volume overload, iron overload (with repeated transfusions), alloimmunization, and transmission of infections (rare)
The decision to transfuse should consider the infant's clinical condition, not just the hemoglobin value alone
Judicious use is encouraged to minimize risks.
Iron Supplementation:
Essential for both ESA therapy and to support ongoing erythropoiesis, especially in iron-deficient premature infants
Intravenous iron is often preferred in NICU settings due to better absorption and fewer gastrointestinal side effects compared to oral iron, particularly in infants with feed intolerance
Doses vary but typically range from 1-4 mg/kg/day
Monitoring for iron overload with prolonged therapy is important.
Supportive Care:
Minimizing blood draws by using microcollection techniques and consolidating laboratory tests
Careful fluid management
Nutritional support to ensure adequate growth and iron absorption
Management of underlying conditions such as infection or coagulopathy
Careful monitoring of vital signs, oxygen saturation, and clinical status.
Erythropoiesis-stimulating Agents Vs Transfusion
Comparison Of Efficacy:
ESAs aim to stimulate endogenous red blood cell production, potentially reducing the need for transfusions and their associated risks
Transfusions provide immediate restoration of hemoglobin but do not address the underlying issue of impaired erythropoiesis
Studies suggest that ESAs can significantly reduce transfusion requirements in preterm infants, particularly when initiated early with adequate iron supplementation.
Comparison Of Risks And Benefits:
Benefits of ESAs include reducing transfusion burden, potential reduction in iron overload, and potentially improved long-term outcomes by allowing for more stable hematocrit levels
Risks include cost, need for concurrent iron supplementation, potential for hypertension or thrombocytosis, and the need for multiple injections
Benefits of transfusion are rapid correction of anemia and improved oxygen delivery
Risks include transfusion reactions, iron overload with repeated transfusions, alloimmunization, and potential for nosocomial infections.
Current Guidelines And Evidence:
Many guidelines recommend using ESAs judiciously in VLBW infants with anemia of prematurity, particularly in those requiring frequent transfusions or with a higher risk of transfusion-related complications
However, the optimal timing, dosage, and duration of ESA therapy remain areas of ongoing research
Consensus guidelines from organizations like the AAP and ESPGHAN provide recommendations for both ESA and transfusion use, emphasizing individualized care and evidence-based decision-making
Recent meta-analyses continue to support the role of ESAs in reducing transfusion needs but highlight the importance of adequate iron provision.
Indications For Choice:
Consider ESAs for prevention and treatment of LAP in stable preterm infants without active infection or significant iron deficiency, especially those likely to require multiple transfusions
Transfusion is the primary treatment for symptomatic anemia, acute significant blood loss, or when ESAs are contraindicated or ineffective
The choice depends on the infant's clinical condition, hemoglobin level, rate of decline, and institutional protocols.
Complications
Complications Of Anemia:
Impaired neurodevelopment and cognitive deficits
Poor growth and failure to thrive
Increased susceptibility to infections
Cardiopulmonary compromise (e.g., heart failure, increased need for respiratory support)
Retinopathy of prematurity (ROP)
Necrotizing enterocolitis (NEC).
Complications Of Transfusion:
Febrile non-hemolytic transfusion reactions
Allergic reactions (urticaria to anaphylaxis)
Volume overload
Acute lung injury (TRALI)
Hemolytic transfusion reactions
Alloimmunization
Graft-versus-host disease (rare)
Transmission of infectious agents
Iron overload (with chronic transfusions).
Complications Of Esa Therapy:
Hypertension
Thrombocytosis
Seizures (rare)
Red cell aplasia (very rare, often associated with antibody formation)
Injection site reactions.
Prevention Strategies:
Minimize blood draws
Use of microcollection techniques
Consider bulk sampling of blood
Optimizing nutrition and iron stores
Prophylactic or early treatment of infection
Judicious use of ESAs with iron supplementation
Careful monitoring for signs of complications.
Prognosis
Factors Affecting Prognosis:
Gestational age and birth weight at birth
Severity of anemia and response to treatment
Presence and severity of comorbidities (e.g., BPD, NEC, sepsis)
Amount of blood transfused
Duration of hospitalization
Adequate nutritional support and iron status.
Outcomes With Treatment:
With appropriate management, the anemia can be corrected, leading to improved growth, development, and reduced long-term morbidities
However, infants who experienced severe or prolonged anemia may have poorer neurodevelopmental outcomes
The goal is to achieve stable hematocrit levels that support adequate oxygenation and growth without excessive transfusion burden.
Follow Up:
Long-term follow-up is essential for all preterm infants, especially those who experienced significant anemia and required interventions
This includes monitoring growth, neurodevelopmental status, and visual function
Hematological follow-up may be required for infants with persistent anemia or iron deficiency.
Key Points
Exam Focus:
Distinguish physiological anemia of infancy from late anemia of prematurity
Understand the multifactorial etiology of LAP
Know the indications for ESAs and transfusions in neonates
Recognize the importance of concurrent iron supplementation with ESAs
Differentiate complications of ESAs versus transfusions
Be aware of the thresholds for intervention.
Clinical Pearls:
Always consider iron status before initiating ESA therapy
Minimize blood draws by planning investigations and using microcollection tubes
A reticulocyte count is a key indicator of bone marrow response
Early intervention with ESAs can reduce the cumulative transfusion volume
Individualize management based on the infant's clinical status, not just lab values.
Common Mistakes:
Initiating ESAs without adequate iron supplementation
Over-transfusing infants who are clinically stable
Failing to recognize occult blood loss as a contributor to anemia
Delaying intervention for symptomatic anemia
Not considering comorbidities when making treatment decisions.