| 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] While the reason for this decreased response is not fully understood, Strauss (n.d.) states that it results from both physiological factors (e.g., the rapid rate of growth and need for a commensurate increase in RBC mass to accompany the increase in blood volume) and, in sick premature infants, from phlebotomy blood losses. In premature infants this decline occurs earlier and more pronounced that it does in healthy term infants. Healthy term infants Hb rarely falls below 9 g/dL at an age of approximately 10–12 weeks, while in premature infants, even in those without complicating illnesses, the mean Hb falls to approximately 8g/dL in infants of 1.0-1.5 kg birth weight and to 7g/dL in infants <1.0 kg. Because this postnatal drop in hemoglobin level is universal and is well tolerated in term infants, it is commonly referred to as the “physiologic” anemia of infancy. However, in premature infants the decline in Hb may be associated with abnormal clinical signs severe enough to prompt transfusions.[ citation needed ]
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]
Anemia or anaemia is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of haemoglobin. When anemia comes on slowly, the symptoms are often vague, such as tiredness, weakness, shortness of breath, headaches, and a reduced ability to exercise. When anemia is acute, symptoms may include confusion, feeling like one is going to pass out, loss of consciousness, and increased thirst. Anemia must be significant before a person becomes noticeably pale. Additional symptoms may occur depending on the underlying cause. Preoperative anemia can increase the risk of needing a blood transfusion following surgery. Anemia can be temporary or long term and can range from mild to severe.
Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to 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.
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 36 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.
Retinopathy of prematurity (ROP), also called retrolental fibroplasia (RLF) and Terry syndrome, is a disease of the eye affecting prematurely born babies generally having received neonatal intensive care, in which oxygen therapy is used due to the premature development of their lungs. It is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. ROP can be mild and may resolve spontaneously, but it may lead to blindness in serious cases. Thus, all preterm babies are at risk for ROP, and very low birth-weight is an additional risk factor. Both oxygen toxicity and relative hypoxia can contribute to the development of ROP.
Infantile respiratory distress syndrome (IRDS), also called respiratory distress syndrome of newborn, or increasingly 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 foetalis, 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. Neonatal refers to the first 28 days of life. Neonatal care, as known as specialized nurseries or intensive care, has been around since the 1960s.
Fetal viability is the ability of a human fetus to survive outside the uterus. Medical viability is generally considered to be between 23 and 24 weeks gestational age. Viability depends upon factors such as birth weight, gestational age, and the availability of advanced medical care. In low-income countries, half of newborns born at or below 32 weeks gestational age died due to a lack of medical access; in high-income countries, the vast majority of newborns born above 24 weeks gestational age survive.
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, bowel death, multiorgan 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 is a human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy.
Apnea of prematurity is defined as cessation of breathing by a premature infant that lasts for more than 20 seconds and/or is accompanied by hypoxia or bradycardia. 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.
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 in the first four weeks of life. Neonatal infections may be contracted by mother to child transmission, in the birth canal during childbirth, or contracted after birth. Some neonatal infections are apparent soon after delivery, while others may develop in the postnatal period. Some neonatal infections such as HIV, hepatitis B, and malaria do not become apparent until much later.
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.