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After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion with a blood type compatible with both the infant and the mother, sodium bicarbonate for correction of acidosis and/or assisted ventilation.
- Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.
- IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
- Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
In cases where oral iron has either proven ineffective, would be too slow (for example, pre-operatively) or where absorption is impeded (for example in cases of inflammation), parenteral iron can be used. The body can absorb up to 6 mg iron daily from the gastrointestinal tract. In many cases the patient has a deficit of over 1,000 mg of iron which would require several months to replace. This can be given concurrently with erythropoietin to ensure sufficient iron for increased rates of erythropoiesis.
In cases of Rho(D) incompatibility, Rho(D) immunoglobulin is given to prevent sensitization. However, there is no comparable immunotherapy available for other blood group incompatibilities.
Early pregnancy
- IVIG - IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone. Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
- Plasmapheresis - Plasmapheresis aims to decrease the maternal titer by direct plasma replacement. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.
Mid to late pregnancy
- IUT - Intrauterine Transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
- Steroids - Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
- Phenobarbital - Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
- Early Delivery - Delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.
Rhesus-negative mothers who have had a pregnancy who are pregnant with a rhesus-positive infant are offered Rho(D) immune globulin (RhIG) at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG. A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunological responses that result in antibody production. Without Rho(D) immunoglobulin, the risk of isoimmunization is approximately 17%; with proper administration the risk is reduced to less than 0.1-0.2%.
Blood transfusions in those without symptoms is not recommended until the hemoglobin is below 60 to 80 g/L (6 to 8 g/dL). In those with coronary artery disease who are not actively bleeding transfusions are only recommended when the hemoglobin is below 70 to 80g/L (7 to 8 g/dL). Transfusing earlier does not improve survival. Transfusions otherwise should only be undertaken in cases of cardiovascular instability.
When treating iron-deficiency anemia, considerations of the proper treatment methods are done in light of the "cause and severity" of the condition. If the iron-deficiency anemia is a downstream effect of blood loss or another underlying cause, treatment is geared toward addressing the underlying cause when possible. In severe acute cases, treatment measures are taken for immediate management in the interim, such as blood transfusions or even intravenous iron.
Iron-deficiency anemia treatment for less severe cases includes dietary changes to incorporate iron-rich foods into regular oral intake. Foods rich in ascorbic acid (vitamin C) can also be beneficial, since ascorbic acid enhances iron absorption. Other oral options are iron supplements in the form of pills or drops for children.
As iron-deficiency anemia becomes more severe, or if the anemia does not respond to oral treatments, other measures may become necessary. In addition to the previously mentioned indication for intravenous iron or blood transfusions, intravenous iron may also be used when oral intake is not tolerated, as well as for other indications. Specifically, for those on dialysis, parenteral iron is commonly used. Individuals on dialysis who are taking forms of erythropoietin or some "erythropoiesis-stimulating agent" are given parenteral iron, which helps the body respond to the erythropoietin agents and produce red blood cells.
The various forms of treatment are not without possible adverse effects. Iron supplementation by mouth commonly causes negative gastrointestinal effects, including constipation. Intravenous iron can induce an allergic response that can be as serious as anaphylaxis, although different formulations have decreased the likelihood of this adverse effect.
Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy. Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyrodoxine (vitamin B). In severe cases of SBA, bone marrow transplant is also an option with limited information about the success rate. Some cases are listed on MedLine and various other medical sites. In the case of isoniazid-induced sideroblastic anemia, the addition of B is sufficient to correct the anemia. Desferrioxamine, a chelating agent, is used to treat iron overload from transfusions.
Therapeutic phlebotomy can be used to manage iron overload.
The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible.
Parenteral iron is increasingly used for anemia in chronic renal disease and inflammatory bowel disease.
Erythropoietin can be helpful, but this is costly and may be dangerous. Erythropoietin is advised either in conjunction with adequate iron replacement which in practice is intravenous, or when IV iron has proved ineffective.
Definitive therapy depends on the cause:
- Symptomatic treatment can be given by blood transfusion, if there is marked anemia. A positive Coombs test is a relative contraindication to transfuse the patient. In cold hemolytic anemia there is advantage in transfuse warmed blood
- In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary.
- In steroid resistant cases, consideration can be given to rituximab or addition of an immunosuppressant ( azathioprine, cyclophosphamide)
- Association of methylprednisolone and intravenous immunoglobulin can control hemolysis in acute severe cases
- Sometimes splenectomy can be helpful where extravascular hemolysis, or hereditary spherocytosis, is predominant (i.e., most of the red blood cells are being removed by the spleen).
Recombinant EPO (r-EPO) may be given to premature infants to stimulate red blood cell production. Brown and Keith (1999) 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. 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 219,857 mm³ while infants that received two dosages only had 173,361 mm³. However, the response to r-EPO typically takes up to two weeks and the higher dosages lead to higher Hb. Brown and Keith (1999) 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.
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. 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. 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.”
Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid a thrombosis, often by starting patients directly on warfarin. For this reason, patients are usually treated with a direct thrombin inhibitor, such as lepirudin or argatroban, which are approved by the FDA for this use. Other blood thinners sometimes used in this setting that are not FDA-approved for treatment of HIT include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.
The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.
In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient's circulation. Those affected should avoid drugs such as aspirin.
Some patients may benefit from removal of the spleen (splenectomy), as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD deficiency.
Other strategies involve the reduction of blood loss during phlebotomy.
Another treatment used is therapeutic strategies. These strategies are aimed at reducing transfusions have assessed the use of strict blood transfusions guidelines and EPO therapy, but reduction of blood loss is most important. For extremely low birth weight infants, laboratory blood testing using bedside devices offers a unique opportunity to reduce blood transfusions. This practice has been referred to as point-of-care testing. Use of these kind of devices to measure the most common ordered blood tests could significantly decrease phlebotomy loss and lead to a reduction in the need for blood transfusions among critically ill premature neonates. A study was done by Adams, Benitz, Geaghan, Kumar, Madan and Widness (2005) to test this theory by conducting a retrospective chart review on all inborn infants <1000g admitted to the NICU during two separate years. 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. 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 instead of blood transfusions and r-EPO.
Treatment is guided by the severity and specific cause of the disease. Treatment focuses on eliminating the underlying problem, whether that means discontinuing drugs suspected to cause it or treating underlying sepsis. Diagnosis and treatment of serious thrombocytopenia is usually directed by a hematologist. Corticosteroids may be used to increase platelet production. Lithium carbonate or folate may also be used to stimulate platelet production in the bone marrow.
Homeopathy, acupuncture, and traditional Chinese medicine should not be used.
Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B.
1- Congenital: 80% are responsive, though the anemia does not completely resolve.
2- Acquired clonal: 40% are responsive, but the response may be minimal.
3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.
Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5-10%) significantly reduce life expectancy.
Effective treatment of the disease has been confined to liver transplants. Success has also been reported with an antioxidant chelation cocktail, though its effectiveness cannot be confirmed. Based on the alloimmune cause hypothesis, a new treatment involving high-dose immunoglobulin to pregnant mothers who have had a previous pregnancy with a confirmed neonatal hemochromatosis outcome, has provided very encouraging results.
Cordocentesis can be performed in utero to determine the platelet count of the fetus. This procedure is only performed if a "prior" pregnancy was affected by . Intrauterine transfusions can be performed during cordocentesis for primary prevention of intracerebral hemorrhage. Any administered cellular blood products must be irradiated to reduce the risk of graft-versus-host disease in the fetus. Additionally, all administered blood products should be reduced-risk ( seronegative and leukoreduced are considered essentially equivalent for the purposes of risk reduction).
If intrauterine platelet transfusions are performed, they are generally repeated weekly (platelet lifespan after transfusion is approximately 8 to 10 days). Platelets administered to the fetus must be negative for the culprit antigen (often -1a, as stated above). Many blood suppliers (such as American Red Cross and United Blood Services) have identified -1a negative donors. An alternative donor is the mother who is, of course, negative for the culprit antigen. However, she must meet general criteria for donation and platelets received from the mother must be washed to remove the offending alloantibody and irradiated to reduce the risk of graft-versus-host disease. If platlet transfusions are needed urgently, incompatible platelets may be used, with the understanding that they may be less effective and that the administration of any blood product carries risk.
The use of Intravenous immunoglobulin () during pregnancy and immediately after birth has been shown to help reduce or alleviate the effects of in infants and reduce the severity of thrombocytopenia. The most common treatment is weekly infusions at a dosage of 1 g/kg beginning at 16 to 28 weeks of pregnancy, depending on the severity of the disease in the previous affected child, and continuing until the birth of the child. In some cases this dosage is increased to 2 g/kg and/or combined with a course of prednisone depending on the exact circumstances of the case. Although this treatment has not been shown to be effective in all cases it has been shown to reduce the severity of thrombocytopenia in some. Also, it is suspected that (though not understood why) provides some added protection from intercranial haemorrhage () to the fetus. Even with treatment, the fetal platelet count may need to be monitored and platelet transfusions may still be required.
The goal of both and platelet transfusion is to avoid hemorrhage. Ultrasound monitoring to detect hemorrhage is not recommended as detection of intracranial hemorrhage generally indicates permanent brain damage (there is no intervention that can be performed to reverse the damage once it has occurred).
Before delivery, the fetal platelet count should be determined. A count of >50,000 μL is recommended for vaginal delivery and the count should be kept above 20,000 μL after birth.
There is increasing use of immunosuppressants such as mycophenolate mofetil and azathioprine because of their effectiveness. In chronic refractory cases, where immune pathogenesis has been confirmed, the off-label use of the "vinca" alkaloid and chemotherapy agent vincristine may be attempted. However, vincristine has significant side effects and its use in treating ITP must be approached with caution, especially in children.
Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction. Two such products are currently available:
- Romiplostim (trade name Nplate) is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody) that is administered by subcutaneous injection. Designated an orphan drug in 2003 under United States law, clinical trials demonstrated romiplostim to be effective in treating chronic ITP, especially in relapsed post-splenectomy patients. Romiplostim was approved by the United States Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.
- Eltrombopag (trade name Promacta in the USA, Revolade in the EU) is an orally-administered agent with an effect similar to that of romiplostim. It too has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner. Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.
Side effects of thrombopoietin receptor agonists include headache, joint or muscle pain, dizziness, nausea or vomiting, and an increased risk of blood clots.
Much like with phototherapy the level at which exchange transfusion should occur depends on the health status and age of the newborn. It should however be used for any newborn with a total serum bilirubin of greater than 428 μmol/l ( 25 mg/dL ).
Corticosteroids can be used to treat anemia in DBA. In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted. Some patients remained responsive to steroids, while efficacy waned in others. Blood transfusions can also be used to treat severe anemia in DBA. Periods of remission may occur, during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can cure hematological aspects of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. However, adverse events from BMTs may exceed those from iron overloading. A 2007 study showed the efficacy of leucine and isoleucine supplementation in one patient. Larger studies are being conducted.
It is unclear if screening pregnant women for iron-deficiency anemia during pregnancy improves outcomes in the United States. The same holds true for screening children who are "6 to 24 months" old.
There is no specific treatment for neonatal hepatitis. Vitamin supplements are usually prescribed and many infants are given phenobarbital, a drug used to control seizures, but which also stimulates the liver to excrete additional bile. Formulas containing more easily digested fats are also given to the infant.
Neonatal hepatitis caused by the hepatitis A virus also usually resolves itself within six months, but cases that are the result of infection with the hepatitis B or hepatitis C viruses most likely will result in chronic liver disease. Infants who develop cirrhosis ultimately will need a liver transplant.
Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."
Summary of transfusion reactions in the US.
Immune thrombocytopenic purpura (), sometimes called idiopathic thrombocytopenic purpura is a condition in which autoantibodies are directed against a patient's own platelets, causing platelet destruction and thrombocytopenia. Anti-platelet autoantibodies in a pregnant woman with immune thrombocytopenic purpura will attack the patient's own platelets and will also cross the placenta and react against fetal platelets. Therefore, is a significant cause of fetal and neonatal immune thrombocytopenia. Approximately 10% of newborns affected by will have platelet counts <50,000 μL and 1% to 2% will have a risk of intracerebral hemorrhage comparable to infants with .
Mothers with thrombocytopenia or a previous diagnosis of should be tested for serum antiplatelet antibodies. A woman with symptomatic thrombocytopenia and an identifiable antiplatelet antibody should be started on therapy for their which may include steroids or . Fetal blood analysis to determine the platelet count is not generally performed as -induced thrombocytopenia in the fetus is generally less severe than . Platelet transfusions may be performed in newborns, depending on the degree of thrombocytopenia.