| Anemia of prematurity | |
|---|---|
| Specialty | Pediatrics  |
Anemia of prematurity (AOP) refers to a form of anemia affecting preterm infants [1] with decreased hematocrit. [2] AOP is a normochromic, normocytic hypoproliferative anemia. The primary mechanism of AOP is a decrease in erythropoietin (EPO), a red blood cell growth factor. [3]
Preterm infants are often anemic and typically experience heavy blood losses from frequent laboratory testing in the first few weeks of life. [4] Although their anemia is multifactorial, repeated blood sampling and reduced erythropoiesis with extremely low serum levels of erythropoietin (EPO) are major causative factors. [5] [6] [7] Blood sampling done for laboratory testing can easily remove enough blood to produce anemia. [4] Obladen, Sachsenweger and Stahnke (1987) studied 60 very low birth weight infants during the first 28 days of life. Infants were divided into 3 groups, group 1 (no ventilator support, 24 ml/kg blood loss), group 2(minor ventilated support, 60 ml/kg blood loss), and group 3(ventilated support for respiratory distress syndrome, 67 ml/kg blood loss). Infants were checked for clinical symptoms and laboratory signs of anemia 24 hours before and after the blood transfusion. The study found that groups 2 and 3 who had significant amount of blood loss, showed poor weight gain, pallor and distended abdomen. These reactions are the most frequent symptoms of anemia in very low birth weight infants. [8]
During the first weeks of life, all infants experience a decline in circulating red blood cell (RBC) volume generally expressed as blood hemoglobin concentration (Hb). [9] As anemia develops, there is even more of a significant reduction in the concentration of hemoglobin. [10] Normally this stimulates a significant increased production of erythropoietin (EPO), but this response is diminished in premature infants. Dear, Gill, Newell, Richards and Schwarz (2005) conducted a study to show that there is a weak negative correlation between EPO and Hb. The researchers recruited 39 preterm infants from 10 days of age or as soon as they could manage without respiratory support. They estimated total EPO and Hb weekly and 2 days after a blood transfusion. The study found that when Hb>10, EPO mean was 20.6 and when Hb≤10, EPO mean was 26.8. As Hb goes down, EPO goes up. [11]
AOP is usually treated by blood transfusion but the indications for this are still unclear. Blood transfusions have both infectious and non-infectious risks associated with them. Also, blood transfusions are costly and may add to parental anxiety. The best treatment for AOP is prevention of worsening of anemia by minimizing the amount of blood drawn from the infant (ie, anemia from phlebotomy). It is found that since blood loss attributable to laboratory testing is the primary cause of anemia among preterm infants during the first weeks of life, it would be useful to quantify blood loss attributable to phlebotomy overdraw (ie, blood collected in excess than what is strictly required for the requested lab tests). Lin and colleagues performed a study to see when and if phlebotomy overdraw was actually a significant problem. [4] They recorded all of the data that could be of influence such as the test performed, the blood collection container used, the infants location (neonatal intensive care unit (NICU) and intermediate intensive care unit), the infant’s weight sampling and the phlebotomist’s level of experience, work shift, and clinical role. Infants were classified by weight into 3 groups: <1 kg, 1 to 2 kg, and >2 kg. The volume of blood removed was calculated by subtracting the weight of the empty collection container from that of the container filled with blood. They found that the mean volume of blood drawn for the 578 tests exceeded that requested by the hospital laboratory by 19.0% ± 1.8% per test. The main factors of overdraw was: collection in blood containers without fill-lines, lighter weight infants and critically ill infants being cared for in the NICU. [4]
Recombinant EPO (r-EPO) may be given to premature infants to stimulate red blood cell production. Brown and Keith studied two groups of 40 very low birth weight (VLBW) infants to compare the erythropoietic response between two and five times a week dosages of recombinant human erythropoietin (r-EPO) using the same dose. [12] They established that more frequent dosing of the same weekly amount of r-EPO generated a significant and continuous increase in Hb in VLBW infants. The infants that received five dosages had higher absolute reticulocyte counts (219,857 mm³) than those infants that received only two dosages (173,361 mm³). However, it was noted that the response to r-EPO typically takes up to two weeks. This study also showed responses between two dosage schedules (two times a week and five times a week). Infants were recruited for gestational age—age since conception—≤27 weeks and 28 to 30 weeks and then randomized into the two groups, each totaling 500 U/kg a week. Brown and Keith found that after two weeks of r-EPO administration, Hb counts had increased and leveled off; the infants who received r-EPO five times a week had significantly higher Hb counts. This was present at four weeks for all infants ≤30 weeks gestation and at 8 weeks for infants ≤27 weeks gestation. [12]
To date, studies of r-EPO use in premature infants have had mixed results. Ohls et al. examined the use of early r-EPO plus iron and found no short-term benefits in two groups of infants (172 infants less than 1000 g and 118 infants 1000–1250 g). All r-EPO treated infants received 400 U/g three times a week until they reached 35 weeks gestational age. The use of r-EPO did not decrease the average number of transfusions in the infants born at less than 1000 g, or the percentage of infants in the 1000 to 1250 group. A multi-center European trial studied early versus late r-EPO in 219 infants with birth weights between 500 and 999 g. An r-EPO close of 750 U/kg/week was given to infants in both the early (1–9 weeks) and late (4–10 weeks) groups. The two r-EPO groups were compared to a control group who did not receive r-EPO. Infants in all three groups received 3 to 9 mg/kg of enteral iron. These investigators reported a slight decrease in transfusion and donor exposures in the early r-EPO group (1–9 weeks): 13% early, 11% late and 4% control group. [13] It is likely that only a carefully selected subpopulation of infants may benefit from its use. Contrary to what just said, Bain and Blackburn (2004) also state in another study the use of r-EPO does not appear to have a significant effect on reducing the numbers of early transfusions in most infants, but may be useful to reduce numbers of late transfusion in extremely low-birth-weight infants. [14] A British task force to establish transfusion guidelines for neonates and young children and to help try to explain this confusion recently concluded that “the optimal dose, timing, and nutritional support required during EPO treatment has yet to be defined and currently the routine use of EPO in this patient population is not recommended as similar reduction in blood use can probably be achieved with appropriate transfusion protocols.” [15]
Other strategies involve the reduction of blood loss during phlebotomy. [16] [17]
For extremely low birth weight infants, laboratory blood testing using bedside devices offers a unique opportunity to reduce blood transfusions. [4] This practice has been referred to as point-of-care testing or POC. Use of POC tests to measure the most commonly ordered blood tests could significantly decrease phlebotomy loss and lead to a reduction in the need for blood transfusions among critically ill premature neonates as these tests frequently require much less volume of blood to be collected from the patient. A study was done by Madan and colleagues to test this theory by conducting a retrospective chart review on all inborn infants <1000g admitted to the NICU that survived for 2 weeks of age during two separate 1 year time periods. [18] Conventional bench top laboratory analysis during the first year was done using Radiometer Blood Gas and Electrolyte Analyzer. Bedside blood gas analysis during the second year was performed using a point-of-care analyzer (iSTAT). An estimated blood loss in the two groups was determined based on the number of specific blood tests on individual infants. The study found that there was an estimated 30% reduction in the total volume of blood removed for the blood tests. This study concluded that there is modern technology that can be used to limit the amount of blood removed from these infants thereby reducing the need for blood product transfusions (or the number of transfusions) and r-EPO. [18]
Intrauterine growth restriction (IUGR), or fetal growth restriction, is the poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's birth weight percentile. The causes of IUGR are broad and may involve maternal, fetal, or placental complications.
Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease and mouth disease.
Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 28 and 32 weeks, early preterm birth occurs between 32 and 34 weeks, late preterm birth is between 34 and 36 weeks' gestation. These babies are also known as premature babies or colloquially preemies or premmies. Symptoms of preterm labor include uterine contractions which occur more often than every ten minutes and/or the leaking of fluid from the vagina before 37 weeks. Premature infants are at greater risk for cerebral palsy, delays in development, hearing problems and problems with their vision. The earlier a baby is born, the greater these risks will be.
Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.
Infant respiratory distress syndrome (IRDS), also known as surfactant deficiency disorder (SDD), and previously called hyaline membrane disease (HMD), is a syndrome in premature infants caused by developmental insufficiency of pulmonary surfactant production and structural immaturity in the lungs. It can also be a consequence of neonatal infection and can result from a genetic problem with the production of surfactant-associated proteins.
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.
A neonatal intensive care unit (NICU), also known as an intensive care nursery (ICN), is an intensive care unit (ICU) specializing in the care of ill or premature newborn infants. The NICU is divided into several areas, including a critical care area for babies who require close monitoring and intervention, an intermediate care area for infants who are stable but still require specialized care, and a step down unit where babies who are ready to leave the hospital can receive additional care before being discharged.
Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an infant of 2,499 g or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal intensive care unit (NICU). They are also at increased risk for long-term health conditions which require follow-up over time.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease that affects premature or very low birth weight infants. Symptoms may include poor feeding, bloating, decreased activity, blood in the stool, vomiting of bile, multi-organ failure, and even death.
In ABO hemolytic disease of the newborn maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.
Hemolytic disease of the newborn (anti-Kell1) is the second most common cause of severe hemolytic disease of the newborn (HDN) after Rh disease. Anti-Kell1 is becoming relatively more important as prevention of Rh disease is also becoming more effective.
Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.
Epoetin alfa, sold under the brand name Epogen among others, is a human erythropoietin produced in cell culture using recombinant DNA technology. Epoetin alfa is an erythropoiesis-stimulating agent. It stimulates erythropoiesis and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Epoetin alfa is developed by Amgen.
Apnea of prematurity is a disorder in infants who are preterm that is defined as cessation of breathing by that lasts for more than 20 seconds and/or is accompanied by hypoxia or bradycardia. Apnea of prematurity is often linked to earlier prematurity. Apnea is traditionally classified as either obstructive, central, or mixed. Obstructive apnea may occur when the infant's neck is hyperflexed or conversely, hyperextended. It may also occur due to low pharyngeal muscle tone or to inflammation of the soft tissues, which can block the flow of air though the pharynx and vocal cords. Central apnea occurs when there is a lack of respiratory effort. This may result from central nervous system immaturity, or from the effects of medications or illness. Many episodes of apnea of prematurity may start as either obstructive or central, but then involve elements of both, becoming mixed in nature.
Clostridial necrotizing enteritis (CNE) is a severe and potentially fatal type of food poisoning caused by a β-toxin of Clostridium perfringens, Type C. It occurs in some developing regions, particularly in New Guinea, where it is known as pig-bel. The disease was also documented in Germany following [World War II]], where it was called Darmbrand (literally "bowel fire," or bowel necrosis). The toxin is normally inactivated by certain proteolytic enzymes and by normal cooking, but when these protections are impeded by diverse factors, and high protein is consumed, the disease can emerge.
Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy.
Erythropoiesis-stimulating agents (ESA) are medications which stimulate the bone marrow to make red blood cells. They are used to treat anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS. In these situations they decrease the need for blood transfusions. The different agents are more or less equivalent. They are given by injection.
Neonatal infections are infections of the neonate (newborn) acquired during prenatal development or within the first four weeks of life. Neonatal infections may be contracted by mother to child transmission, in the birth canal during childbirth, or after birth. Neonatal infections may present soon after delivery, or take several weeks to show symptoms. Some neonatal infections such as HIV, hepatitis B, and malaria do not become apparent until much later. Signs and symptoms of infection may include respiratory distress, temperature instability, irritability, poor feeding, failure to thrive, persistent crying and skin rashes.
Neonates are defined as babies up to 28 days after birth. Most extremely preterm babies require at least one red cell transfusion; this is partly due to the amount of blood removed with blood samples compared to the baby's total blood volume and partly due to anemia of prematurity. Most transfusions are given as small volume top-up transfusions to increase the baby's hemoglobin above a certain pre-defined level, or because the baby is unwell due to the anemia. Possible side-effects of anemia in babies can be poor growth, lethargy and episodes of apnea. Exchange blood transfusion is used to treat a rapidly rising bilirubin that does not respond to treatment with phototherapy or intravenous immunoglobulin. This is usually due to hemolytic disease of the newborn, but may also be due to other causes, e.g., G6PD deficiency.
Iatrogenic anemia, also known as nosocomial anemia or hospital-acquired anemia, is a condition in which a person develops anemia due to medical interventions, most frequently repeated blood draws. Other factors that contribute to iatrogenic anemia include bleeding from medical procedures and dilution of the blood by intravenous fluids. People may receive blood transfusions to treat iatrogenic anemia, which carries risks for complications like transfusion reactions and circulatory overload.