- Anemia Update in Pregnancy
- Pregnancy after Corrected Heart Disease
- An Update on TORCH-S Infections
- Obstetric Admissions to ICU
- Liver Disorders in Pregnancy: Current Evidence for Management
- Changing Scenario in the Management of Placenta Previa Accreta
- Postpartum Complications
- Anesthetic Considerations and Obstetric Outcomes
- Ultrasonography: Special Situations
INTRODUCTION
Anemia is one of the most commonly encountered medical disorders during pregnancy. In developing countries it is a cause of serious concern as it contributes to high maternal mortality. According to United Nations declaration 1997, anemia is a major public health problem that needs total elimination. It is estimated that globally two billion people suffer from anemia or iron deficiency.1
PREVALENCE OF ANEMIA IN PREGNANCY
According to World Health Organization estimates, up to 56% of all women living in developing countries are anemic.2 In India, National Family Health Survey-II in 1998 shows that 54% of women in rural and 46% women in urban areas are anemics.3 The prevalence of anemia globally is shown in Table 1-1.
The relative prevalence of mild, moderate, and severe anemia is 13%, 57% and 12% respectively in India (ICMR data) Table 1-2.
According to WHO, hemoglobin level below 11 g/dl in pregnant women constitutes anemia and hemoglobin below 7 g/dl is severe anemia. The Center for Disease Control and Prevention (1990) defines anemia as less than 11 g/dl in the first and third trimester and less than 10.5 g/dl in second trimester. 4,16 Serum ferritin level of 15 μg/L is associated with iron deficiency anemia.8,16
ERYTHROPOIESIS IN PREGNANCY8
The various factors required for erythropoiesis are proteins (erythropoietin), minerals (iron), trace elements (including zinc, cobalt and copper), vitamins (particularly folic acid, vitamin B12, vitamin C, pyridoxine, and riboflavin), and hormones (androgens and thyroxine).4
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In addition to the common deficiencies of iron and folate, there is a growing body of evidence to implicate vitamin A (important for cell growth and differentiation, maintenance of epithelial integrity and normal immune function) and zinc (important in protein synthesis and nucleic acid metabolism) in nutritional anemias.6,8
Anemia is a condition of low circulating hemoglobin (Hb) in which concentration has fallen below a threshold lying at two standard 5deviations below the median of a healthy population of the same age, sex and stage of pregnancy. The WHO definition for diagnosis of anemia in pregnancy is a Hb concentration of less than 11 g/dl (7.45 mmol/L) and a hematocrit of less than 33%.9
Causes of Anemia
The causes of anemia are delineated in Figure 1-1.10
Physiological Anemia
During pregnancy there is a disproportionate increase in plasma volume, RBC volume and hemoglobin mass. As plasma volume increases more than the RBC mass, hemodilution occurs and is called physiological anemia of pregnancy.
Criteria are:
- RBC 3.2 million/cc
- Hemoglobin 10 g%
- RBC morphology on peripheral smear is normal, i.e. normocytic, normochromic.
- PCV 30%.
Iron Deficiency Anemia
About 1000 mg of iron is required during pregnancy;11 500–600 mg for RBC expansion, 300 mg for fetus and placenta and the rest for the growing uterus. As a result of amenorrhea there is a sparing of about 150 mg of iron and therefore, about 850 mg of extra iron is required during pregnancy. Diet alone cannot provide the extra iron and stores 6which have around 500 mg of iron get depleted. But if iron stores are already deficient, iron deficiency anemia manifests.
Iron deficiency anemia (IDA) is the commonest type of anemia in pregnancy.12 Iron nutritional status depends on long-term iron balance and is favored by ingestion of adequate amounts of iron in the diet (native or fortified) or through iron supplementation as shown in Table 1-3. The balance is adversely affected by the loss of iron through intestinal mucosal turnover and excretion, skin desquamation, menstruation and lactation.13 Iron absorption which is 15—30% (heme iron) and up to 50% in the iron deficiency state reduces to 5—8% with an excessive haem diet. Its absorption is usually not affected by inhibitors. The non-heme iron pool is made of all other sources of iron such as cereals, seeds, vegetables, milk and eggs. Its absorption can be increased by enhancers (heme, proteins, ascorbic acid and fermentation) and decreased by inhibitors (phytic acid, fibers, calcium, tannins, tea, coffee, chocolate and herbal infusion).8,14 The factors affecting the iron status of a pregnant woman are shown in Table 1-3.
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Low bio-availability dietsSimple diet containing beans, whole wheat flour and sorghum with negligible amounts of meat, fish and ascorbic acid cause nutritional anemia. In non-industrialised countries, a very low-bio-available iron, vegetarian diet low in ascorbic acid and high in biological proteins composed almost entirely of cereals is consumed with excess of inhibitors of iron absorption (phytates); thus, absorption may be as low as 3.4%.21Intermediate bio-availability dietDiets in this category are mainly comprised of cereals, roots or tubers, but include some animal foods like meat, fish and ascorbic acid which increase iron absorption.High bio-availability dietThis is a varied diet rich in meat, poultry, fish and foods with a generous amount of ascorbic acid, as found in industrialized countries.
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Prevalence of amebiasis and giardiasis is around 40%. Increased iron loss due to hookworm infestations, schistosomiasis, chronic malaria, and blood loss from the gut due to hemorrhoids are important causes of anemia in pregnancy.
- Multiple pregnanciesMost women enter pregnancy with little or no iron reserve, which is further compounded by repeated and closely spaced pregnancies and prolonged periods of lactation.
Prevention of Iron Deficiency
Prophylaxis of non-pregnant women
As most women start their pregnancy with anemia or low iron stores, prevention should start even before pregnancy. As a public health approach, prolonged oral supplementation beginning before the woman becomes pregnant may be a better strategy to benefit the majority of the population. Iron supplementation by 30 doses administered weekly over seven months was as effective as 90 doses consumed daily for three months. Hence, women of child-bearing age in developing countries should receive a two-four months course of 60 mg of iron daily. In addition, concomitant use of folate will prevent neural tube defects in the newborn.8
Iron supplementation during pregnancy
The Ministry of Health, Government of India has now recommended an intake of 100 mg of elemental iron with 500 mg of folic acid in the second half of pregnancy for a period of at least 100 days. Women who receive daily antenatal iron supplementation are less likely to have iron deficiency anemia at term. Even two injections of iron dextran (250 mg each) given intramuscularly at four-week intervals along with tetanus toxoid injection have been recommended for better compliance and adequate results.
Treatment of hookworm infestation15
As worm infestation is very common and given the safety of deworming drugs, oral antihelminthic treatment can also be given to pregnant and lactating women. Single albendazole (400 mg) or mebendazole (100 mg) doses twice daily for three days with iron supplementation should be given to all anemic pregnant women in the second and third trimesters for better results.
Improvement of dietary habits and improving the bio-availability of food iron13
All pregnant women should eat foods rich in iron (jaggery, green leafy vegetables like spinach, mustard leaves, turnip greens, cereals, and sprouted pulses)and cook their food in iron utensils. Too much of cooking should be avoided. This improves bioavailability of dietary iron.
Social services
Improvement of sanitation, personal hygiene, better education and alleviation of poverty should be looked into with the support of social and political help.
Food fortification
Iron fortification of food is a preventive measure that aims at improving and sustaining iron nutrition on a permanent basis. Many countries fortify a cereal product of fish sauce, sugar or curry powder with iron compounds like ferrous sulphate, ferrous gluconate, ferrous fumarate, ferrous succinate or chelated iron compounds such as, bovine hemoglobin concentrate and Fe-Na-EDTA.6 Even common salt, which is often fortified successfully with iodine in deficient areas, can be fortified with iron as has been successfully done in various South-East Asian and Latin American countries. Production of iron fortified salt on a commercial scale has been approved by the Government of India and is in the process of manufacture.209
Effects of Anemia on Pregnancy
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Mild anemia may not have any effect on pregnancy and labor except that the mother will have low iron stores and may become moderately-to-severely anemic in subsequent pregnancies. Moderate anemia may cause increased weakness, lack of energy, fatigue and poor work performance. Severe anemia, however, is associated with complications. These women may have palpitations, tachycardia, breathlessness, increased cardiac output leading on to cardiac stress which can cause de-compensation and cardiac failure which may be fatal.5,8 Increased incidence of pre-term labor (28.2%), pre-eclampsia (31.2%) and sepsis have been associated with anemia.5
- Fetal effectsIrrespective of maternal iron stores, the fetus still obtains iron from maternal transferrin, which is trapped in the placenta and which, in turn, removes, and actively transports iron to the fetus. Gradually, however, such fetuses tend to have decreased iron stores due to depletion of maternal stores. Adverse perinatal outcome in the form of pre-term and small-for-gestational-age babies and increased perinatal mortality rates have been observed in the neonates of anemic mothers. Iron supplementation to the mother during pregnancy improves perinatal outcome. Mean weight, Apgar score and hemoglobin level three months after birth were significantly greater in babies of the supplemented group than the placebo group.
Clinical Features of IDA
Symptoms
There may be no symptoms, especially in mild and moderate anemia. Patient may complain of feelings of weakness, exhaustion and lassitude, indigestion and loss of appetite. Palpitation, dyspnea, giddiness, edema and, rarely, generalized anasarca and even congestive cardiac failure can occur in severe cases.
Signs
There may be no signs especially in mild anemia. There may be pallor, glossitis and stomatitis. Patients may have edema due to hypoproteinemia. Soft systolic murmur can be heard in mitral area due to hyperdynamic circulation.10
Diagnosis
Hemoglobin estimation is the most practical method of diagnosis as it is cost effective and can be easily performed by trained technician. The Taliquist´s method of Hb estimation has simplicity and easy applicability, but is not very accurate. Sahli´s method is reliable and accurate when done by expert, and is the most commonly used method, although the cyanomethemoglobin method appears to be the most accurate.
Peripheral blood film is another bedside indicator for diagnosis of anemia which will also differentiate between iron deficiency anemia, megaloblastic anemia and hemolytic anemia. In iron deficiency anemia, there is microcytosis, hypochromia anisocytosis, poikilocytosis and target cells in the blood film. Iron deficiency anemia must be differentiated from thalassemia as shown in Table 1-4.
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Serum ferritin level below 12 μg/L is taken to indicate iron deficiency. It is stable, unaffected by recent iron intake, reflects iron stores accurately, and is the first abnormal laboratory test in iron deficiency.
Serum iron varies from 60—120 μg/dl while TIBC is 300—350 μg/dl, (increased to 300—400 μg/dl in pregnancy). Serum iron of less than 60 μg/dl, TIBC of more than 350 μg/dl and transferrin saturation of less than 15% indicates deficiency of iron during pregnancy (Table 1-5).11
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Free erythrocyte protoporphyrin (FEP) is the third estimation of Iron status rising with defective iron supply to the developing red cells and takes 2–3 weeks to become abnormal after depletion of iron stores. It also helps in differentiation between iron deficiency anemia and thalassemia.23
Serum transferrin receptor appears to be specific and sensitive marker of iron deficiency in pregnancy. Its levels are increased in iron deficiency anemia. Bone marrow examination by staining with potassium ferrocyanate to see characteristic blue granules of stainable iron in erythroblasts is the most accurate method for iron stores, but is not practical in most cases as the test is invasive. Bone marrow examination is only indicated in cases where there is no response to iron therapy after 4 weeks or for diagnosis of kala azar or in suspected aplastic anemia.11 As worm infestations are common causes of anemia, stool examination for ova and cysts should be done consecutively for 3 days in all cases. In areas where schistosomiasis is prevalent, urine examination for occult blood and schistosomes should be performed. As malaria is an important cause of anemia, peripheral blood should be examined for malarial parasites. Significant bacteriuria should also be ruled out. If the clinical scenario demands, other tests can be done, such as sputum examination and chest X-ray for pulmonary tuberculosis (abdominal shielding should be done), renal function tests in suspected renal disease and serum proteins in hypoproteinemia.22
Management of IDA
In developing countries, it is common to see patients of moderate and severe anemia late in pregnancy. They have had nil or inadequate antenatal care and have not taken iron supplements in pregnancy. If the woman presents in mid-trimester or early third trimester, oral iron is started.12
For treatment, Government of India, Ministry of Health recommends 100 mg of elemental iron with 0.5 mg folic acid twice a day or elemental iron of 180 mg. This may cause increased incidence of side-effects thus some recommend 120 mg elemental iron per day. Ferrous ascorbate is the most favorable iron for Indian diet which his high content of inhibitors for iron absorption.12 One needs to change a brand only when the patient cannot tolerate it. Addition of folic acid, but not vitamin B12 helps in improving the results in supervised supplementation. Up to 10% of women may have side-effects with oral iron in the form of gastrointestinal symptoms such as nausea, vomiting, constipation, abdominal cramping and diarrhea which are dose-related. The treatment of choice is to reduce the dose. If this does not work, another preparation (carbonyl) iron or hemoglobin preparations may be better tolerated.
Response to Therapy
Feeling of well being, improved look and better appetite is the clinical response. Hematologically, there is reticulocyte response in 5–10 days with a rise in Hb concentration from 0.3 g to 1.0 g per week and hematocrit subsequently. If there is no significant clinical or hematological improvement within 3 weeks, diagnostic re-evaluation is needed.
Reasons for failure to respond to oral therapy are inaccurate diagnosis (non-iron deficiency, microcytic anemia, such as thalassemia, pyridoxine deficiency and lead poisoning), non-compliance, continuous loss of blood through hook worm infestation or bleeding hemorrhoids, co-existing infection, faulty iron absorption and concomitant folate deficiency. Iron content in different salts is shown in Table 1-6.
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Newer Iron Preparations
- Iron Amino Acid ChelatesThese are conjugates of ferrous or ferric ions with amino acids. Ferrous glycine sulphate is the only iron amino acid chelate available in India. Its main advantage is its relatively high bioavailability in the presence of dietary inhibitors. The chelates prevents iron from binding inhibitors in food or precipitating it as an insoluble complex in the gut.Sustained release preparations like iron polymaltose complex (IPC) and Iron hydroxide polysucrose complex are available. These have nonionic iron in a stable complex. Absorption is not affected by food or milk and these can be given with food. It has better absorption and lesser side effects than ferrous salt.
- Carbonyl IronIt is pure form of elemental iron which has low toxicity and is tolerated in larger doses when compared to ferrous salts. Carbonyl iron refers to manufacturing process whereby pentacarbonyl iron is reduced by heating to very fine microsphere of less than 5 microns in diameter which are better absorbed and associated with lesser gastrointestinal side effects. It is available as modified release preparations.While selecting iron preparations for therapy, it is important to bear in mind that modified release formulations release iron gradually as they pass along the gut hence, a part of the iron is released beyond the most actively absorbing regions of the intestines, that is the first part of the duodenum, thereby reducing overall absorption of iron.Of all the iron preparations, ferrous sulphate, ferrous fumarate and ferrous ascorbate are the preferred formulations.
Parenteral Iron Therapy
The rise in Hb concentration is the same, as with oral iron (up to l g per week).
Indications
- Poor tolerance to oral therapy.
- Poor absorbtion of iron like in chronic diarrhea, ulcerative colitis, celiac disease or inflammatory bowel disease.
- Non-compliance.
- Oral iron is not effective.
- Women near term with severe anemia.
- Presence of concurrent disease like chronic renal failure, when patient is on hemodialysis or being treated with erythropoietin.
Preparations
- Parenteral iron is available as iron dextran complex (Imferon) which can be given intramuscularly or intravenously.
- Iron sorbitol citric acid complex (Jectofer) can only be given, intramuscularly. Jectofer plus contains folic acid and vitamin Bl2 along-with elemental iron.
- Iron sucrose complex (Venofer). Each ml has 20 mg of elemental iron.
- Iron gluconate is available as sodium ferric gluconate (ferrlecit).
Deficit is calculated as:
Elemental iron needed (mg) = (Normal Hb — Patient's Hb) × Weight (kg)× 2.21 + 1000
Here, normal hemoglobin is taken as 14% and 2.21 is standard coefficient. To the value calculated by above formula, 1000 mg is added for the stores.
Technique of Giving Parenteral Iron
Intravenous route
Before giving test dose it is essential to have all the resuscitation equipment and drugs ready.
Iron dextran (Imferon) is diluted in normal saline or 5% dextrose and given slowly initially.22 If there is no reaction, it can be given faster. If the calculated dose is more than 2500 mg, it should be even in 2 doses on two consecutive days. One should look for any reaction in the form of chest pain, rigor, chills, fall in blood pressure, dyspnea and anaphylactic reaction.22 For any such reaction, infusion should stopped and antihistaminic, corticoids and epinephrine given.
Intramuscular route
This is more popular and is associated with less side effects. For giving intramuscular injection it is important to test for hypersensitivity. Full dose of iron can be given daily on alternate buttocks by deep intramuscular injection by Z technique. Oral iron should be stopped before, giving iron sorbitol as it is associated with toxic reaction such as headache, nausea and vomiting. Disadvantages of intramuscular iron include pain, sterile abscess formation, nausea, vomiting, headache, fever, lymphadenopathy, allergic reactions and rarely anaphylaxis.15
Blood transfusion
Blood transfusion is required in patients with severe anemia beyond 36 weeks, associated infection, to replenish blood loss due to ante-partum or post-partum hemorrhage and in patients not responding to oral or parenteral iron therapy. Packed cells are preferred for transfusion. Blood: transfusion can cause transfusion reaction, precipitate preterm labor and, rarely, overload the heart.17,22
Iron Dextran
It is stable parenteral iron product with a molecular weight of 100 to 500 kDa. The stability of iron dextran complex allows administration of high single dose in total dose therapy.
Iron Gluconate
This is labile type of iron compound with fast degradation kinetics and iron is released directly to the plasma proteins like apotransferrin, apoferritin and others. About 80% of the iron supplied as iron gluconate is delivered to transferrin in 24 hours.
Iron Sucrose Complex
It is a smaller molecule than iron dextran being only 36 to 60 kDa and hence, carries no risk of anaphylaxis. The iron released is partially taken up by plasma proteins like apoferritin and partially by reticuloendothelial system.
We have performed studies on role of parenteral iron (iron sucrose) alone or in combination with erythropoietin at AIIMS and found a rise in Hb of 1.5 g with parenteral iron alone as compared to 3.0 g in combination with parenteral iron and erythropoietin.
One single regimen is as follows:
Inj. iron sucrose (FerriS, Hemfer) 200 mg IV injection every alternate day for 5–10 injections depending upon the deficit in hemoglobin. Usually, there is no reaction with iron sucrose but still it is better to keep injection of adrenaline, hydrocortisone and oxygen, etc. ready.
Inj. iron sucrose plus inj. erythropoietin (Epofer) 4000–6000 unit subcutaneously every other day for 3 doses (total about 18000 units).
Recombinant Erythropoietin
The stimulation of erythropoiesis with rhEPO is a highly promising alternative to blood transfusion.16
Dosage Regimen Erythropoietin (Epofer)
Inj erythropoietin can be given subcutaneously or IV 100—150 IU/kg on day 1, 3 and 5 along with parenteral iron or day 1, 3 and 5,6000 units SC erythropoietin iron dextran 100 mg deep IM daily for 5 days.
Dose should be given after subcutaneous sensitivity test. Adrenaline, hydrocortisone and oxygen to be kept ready.
Antenatal Care
The antenatal management is like any other case, but more frequent visits are required. One should be vigilant to detect and manage complications of anemia, such as heart failure or preterm labor, as early as possible. Fetal monitoring for growth and wellbeing should be done as these fetuses tend to be small. Prognosis is good if anemia is detected and treated in time. Management of a case of severe anemia is given in Figure 1-2.
Fig. 1-2: Summary protocol of severe anemia in pregnancy22
Management of Labor in Anemic Patient
In the first stage, the patient should be in a comfortable position. Sedation and pain relief should be given. Oxygen should be kept ready and is given in dyspnea. In cases of preterm labor, betamimetics and steroids should be given with caution to avoid the risk of pulmonary edema. Digitalization may be required in cardiac failure due to severe anemia. The aim is to deliver the baby vaginally. Antibiotic prophylaxis is preferred. The second stage is the most stressful, when the patient can go into cardiac failure. A tendency for prolongation of the second stage can be curtailed by forceps. Active management of the third 17stage should be done except in very severe anemia for fear of cardiac failure. However, any post-partum hemorrhage must be frenetically treated as these patients tolerate bleeding very poorly17,22 Maternal mortality in severe anemia can occur in the last trimester, during labor, immediately after delivery and during puerperium due to cardiac failure or pulmonary embolism.
Puerperium
The mother should have adequate rest; iron and folate therapy should be continued for least 3 months. Any infection must be treated. Puerperal sepsis, failing lactation, subinvolution of uterus and thrombo-embolism are more common in these patients and should be carefully watched for.
Contraception
The anemic patient must use an effective method of contraception and should not conceive for at least 2 years giving time for iron stores to recover. Sterilization is preferred if the family is completed. If there is no history of menorrhagia, an intrauterine device can be inserted. Barrier methods can be safely given, but their higher failure rate is a disadvantage.
MEGALOBLASTIC ANEMIA IN PREGNANCY
The low incidence of megaloblastic anemia during pregnancy is because of the abundance of both folic acid and vitamin B12 in the vegetarian and nonvegetarian diet. In the developing world, the incidence is considerably higher, approximately 25% of women affected with anemia during pregnancy.
In megaloblstic anemia, DNA replication is affected. There is derangement of red cell maturation with production of abnormal precursors known as megaloblasts which can be due to deficiency of folate or vit B12.22,23
Usually, it has an insidious onset with gradually progressive symptoms and signs of anemia, i.e. weakness, easy fatigability, tiredness, etc. Gastrointestinal symptoms like anorexia, nausea, vomiting, diarrhea and glossitis are more common. Hyperpigmentation of skin and oral mucosa, palpable liver and spleen, petechial rash due to thrombocytopenia may be present and in such cases, leukemia and aplastic anemia should be ruled out.
Nail changes do not occur in megaloblastic anemia. If occurs more commonly in multiple pregnancies, develops late in pregnancy around 20–28 weeks, develops immediately postpartum or up to fifth month, in OC pill users or in antiepileptic drug users.
The cause of megaloblastic anemia in pregnancy is nearly always due to the deficiency of folate which leads to wasting and hematological symptoms. If post-delivery hemoglobin level falls rapidly and there is no history of excessive blood loss then suspicion of folic acid deficiency is aroused first. Folic acid in pregnancy is not always accompanied by significant hematological changes. In the absence of changes, megaloblastic hematopoiesis is suspected when expected response to adequate iron therapy is not achieved. Ultimately diagnosis is dependent on marrow examination and the finding of large erythroblasts and giant abnormally shaped metamyelocytes.
As such vitamin B12 deficiency takes years to develop anemia and its deficiency causes infertility thus megaloblastic anemia due to B12 deficiency is very rare in pregnancy. Neurological features are more pronounced and if any autoimmune disease exists in the body with anemia then suspicion of B12 megaloblastic anemia arises.
Criteria for Megaloblastic Anemia
At least two of the following criteria must be present:
- More than 4% of neutrophil polymorphs have five or more lobes.
- Orthochromatic macrocytes must be present with diameter > 12 mm.
- Howell-Jolly bodies are demonstrated.
- Nucleated red cells.
- Macro polycytes may be present.
Folate Deficiency
Effects on Pregnancy
There is increased incidence of abortion, growth retardation, placental abruption and pre-eclampsia in folate deficiency in some, but not all studies.23 Folate supplements during pregnancy have resulted in increased birth weight in cases of malnutrition.
Effects on Fetus
Neural tube defects can be prevented in most cases by periconceptional folic acid in dosage of 0.4 mg/day in low-risk cases and 5 mg/day in 19high-risk women. Incidence of neural tube defects is very high in India and periconceptional folate supplementation is strongly recommended in all cases for at least 12 weeks before conception. There is some evidence that the incidence of abortion, premature babies, small-for-date babies and folate deficiency in the neonates is higher in babies born to mothers with folate deficiency.22,23
Investigations
Laboratory findings consist of a fall in Hb concentration to generally < 10 g/dl, MCV > 96 fl, MCH > 0.33 pg, and normal MCHC. There is macrocytic anemia: with hypersegmentation of neutrophils, neutropenia and thrombocytopenia on peripheral blood film. A combination of low serum folate (<3 mg/ml) and red cell folate (<150 ng/ml is diagnostic of folic acid deficiency. Serum iron is usually normal or high. Increased formiminoglutamic acid (FIGLU) in urine following a loading dose of histidine is found in folate deficiency, but the test is rarely done these days.24.25 Serum lactic dehydrogenase (LDH) and homocysteine levels are elevated in folate deficiency. The deoxyuridine suppression test helps in differentiating between folate and vitamin B12 deficiency. Bone marrow will show a megaloblastic picture, but is rarely required.
Prophylaxis
The WHO recommends a daily folate intake of 800 μg in the antenatal period and 600 μg during lactation. However, 300–500 μg present in most iron preparations is enough for prophylaxis.26,27 Pregnant women should eat more green vegetables (e.g. spinach and broccoli), offal (e.g. liver and kidneys). Folate is destroyed by cooking. Even food fortification with folic acid is recommended and is already in use in Western countries.
Treatment
Treatment of established folic acid deficiency by giving 5 mg oral folate per day should be continued for at least 4 weeks in puerperium. By 4–7 days of therapy, the reticulocyte count is appreciably increased.
Vitamin B12 Deficiency
Pernicious anemia caused by lack of intrinsic factor resulting in lack of absorption of vitamin B12 is rare during pregnancy as it usually causes infertility. Women with gastrectomy and ileal disease and 20resection can have vitamin B12 deficiency. Acquired vitamin B12 deficiency causing megaloblastic anemia is also uncommon, as the daily requirement of vitamin B12 is only 3.0 μg during pregnancy which is easily met with a normal diet.28 Only vegetarians who do not eat any animal-derived substance may have a deficiency of vitamin B12 and they should have their diet supplemented during pregnancy. Infestations with Diphyllobothrium latum in some countries can cause megaloblastic anemia due to competitive utilization of ingested vitamin B12 by the parasite
Investigations
Findings are the same as in folate deficiency. Vitamin B12 levels are lower in blood (<90 μg/L). Serum methyl malonic acid is elevated in vitamin B12 deficiency. Serum homocysteine is elevated in both folate and vitamin B deficiency. The deoxyuridine suppression test can differentiate between vitamin B12 and folate deficiency. Schilling test is done to diagnose pernicious anemia.
Treatment
Parenteral cyanocobalamin (250 μg) is given intramuscularIy every month.
Hemolytic Anemias
Hemolytic anemias may occur because of erythrocyte defects such as abnormalities of hemoglobin structure, metabolic disturbances, or membrane abnormalities.29 Almost all erythrocyte defects causing hemolysis are hereditary in nature. Hemolysis may also occur due to the presence of substances in the plasma that attack and destroy the erythrocyte such as in autoimmune hemolytic anemia. A normal red cell lives for about 120 days. This life span is shortened in the case of hemolytic anemias because of premature destruction of red cells, which may occur extravascularly (i.e acquired immune hemolytic anemia) or intravascularly (i.e. microangiopathic hemolytic anemia of pre-eclampsia). Although classifications of anemias according to the site of hemolysis is important for an adequate interpretation of the laboratory tests for differential diagnosis, in many hemolytic destruction occurs in both compartments and laboratory tests are ambiguous.21
Extravascular hemolysis is the most common hemolytic anemia. The red cells are destroyed in the reticuloendothelial system, hemoglobin is converted to bilirubin. An increase in indirect bilirubin is apparent in the patient´s serum. The products of bilirubin metabolism, fecal and urinary urobilinogen, also increase. Erythropoiesis increases markedly, and reticulocytosis occurs. Thus, elevated unconjugated bilirubin, increased urinary urobilinogen, and reticulocytosis are the laboratory hallmarks of extravascular hemolysis.
Intravascular and extravascular hemolysis both cause bone marrow response characterized by marked erythroid hyperplasia and reticulocytosis. In some cases, the erythropoiesis is so active that there is passage of immature cells into the bloodstream. Also, in all cases of accelerated red cell destruction, plasma-lactic dehydro (LDH) increases as a consequence of the liberation LDH isoenzyme from the red cells.
The most common form of hemolytic anemia seen during pregnancy is the intravascular microangiopathic hemolysis, which is a part of the HELLP syndrome. More infrequently the obstetrician sees the hemolytic anemia associated with defects in hemoglobin structure, particularly sickle cell disease (SCD). The World Health Organization (WHO) estimates that globally at least 5% of adults are carriers for a hemoglobin condition: approximately 2.9% for thalassemia and 2.3% for sickle cell disease.
Microangiopathic Hemolytic Anemia
Microangiopathic hemolytic anemia occurs during pregnancy in patients with a severe form of pre-eclampsia, HELLP syndrome. The differential diagnosis in pregnant women can be thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). All of these show fragmented red cell, schistocytes, and burr cells. Thrombocytopenia is always present. Delivery improves clinical and laboratory parameters in HELLP but not in HUS.
Hemolytic Anemias Associated with Hemoglobinopathies
Sickle cell disease (SCD) is the most common hemoglobinopathy encountered during pregnancy because of the severity of the applications associated with this condition. Pregnancy with sickle cell disease is a high risk pregnancy and management should be multidisciplinary to give optimal maternal and neonatal outcome. SCD is an autosomal recessive condition caused by the substitution of valine 22for glutamine in position 6 in the beta-globin chain of the hemoglobin molecule, resulting in the proteins of sickle cell hemoglobin, or HbSS. The condition affects 0.2% of the African-American population of USA. In India it is common in the tribal population of central India.29 The disease is characterized by chronic hemolytic anemia and by the occurrence of acute, life-threatening occlusive crisis. It is associated with increased maternal and perinatal morbidity and mortality.
Sickle Cell Trait
The heterozygous inheritance of the gene for hemoglobin S results in sickle-cell trait, or AS hemoglobin. The trait is not associated with increased abortion, perinatal mortality, low birth weight, or pregnancy-induced hypertension. Sickle cell trait, therefore, should not be considered a deterrent to pregnancy on the basis of increased maternal risks.29,30
In SCD when HbS is oxygenated, its solubility is similar to that of normal hemoglobin (HbSS) but in the deoxy form solubility decreases and in a reduced oxygen environment the HbSS will polymerize into long tube-like fibers, which causes morphological changes characterized by sickling of the erythrocytes. The abnormal erythrocytes are removed and destroyed in the reticuloendothelial system, resulting in chronic extravascular hemolysis. HbF inhibits the polymerization of HbSS and patients with elevated levels of HbF have milder forms of the disease.
In certain situations such as increased deoxygenation, prolonged capillary transit time is increased. Concentration of corpuscular hemoglobin, and acidosis, clusters of sickle cells occlude the microvasculature, producing ischemic infarction and severe inflammatory reactions that clinically translate into a painful sickle cell crisis. Around 14.2% of all pregnancies in patients with SCD end with the delivery of stillborn infants and neonatal morality is approximately 84.5 per 100 live births. Another study shows a perinatal mortality as low as 11.0%. The frequency of infants with birth weights less than 2500 g in patients with SCD is increased.
Acute chest syndrome is the most common cause of mortality in patients with SCD. It is characterized by chest pain, respiratory distress with tachypnea, coughing and wheezing, fever, and decreased oxygen saturation.
Infection is a frequent-cause of sickle cell crisis but diagnosis is difficult because many of the signs and symptoms of a vaso-occlusive 23crisis are similar to those of infection. Fever, leukocytosis, elevated bilirubin, and LDH are also components of crises. Relief of the severe pain, reduction in HbSS concentration and increased oxygen supply to the tissues are the goals of management. Treatment usually involves pain management, oxygen, antibiotics, incentive spirometry, bronchodilators, and in most cases transfusion therapy.
Prenatal Diagnosis
Women with sickle cell trait should have preconception counseling, and the male partner should be examined to determine whether or not he also carries the trait. If the father is a carrier, there is a 25% chance that the infant will be homozygous and have SCD. In this situation, early prenatal genetic diagnosis is important because it will allow the possibility of pregnancy termination. Early prenatal diagnosis is possible with the use of polymerase chain reaction (PCR), amniocentesis or chorion villous sampling.30–32
Antepartum Care
- Close observation
- Folic acid supplementation
- Identify sickle cell crisis—adequate hydration to be maintained
- Screening and treatment for bacteriuria
- Assessment of fetal health—weekly ante partum fetal surveillance beginning at 32 to 34 weeks with serial ultrasonography to monitor fetal growth and amniotic fluid
- Prophylactic transfusions in women with a history of multiple vaso-occlusive episodes and poor obstetrical outcomes.
Patients with SCD do not require iron supplements during pregnancy, unless laboratory evidence of iron deficiency is obtained. In contrast, they need adequate folic acid supplementation to compensate for the increased consumption of folate secondary to the active process of cell replication that takes place in their bone marrow.
Labor and Delivery
- Adequate analgesia
- Epidural analgesia-ideal
- Compatible blood should be available
- If hematocrit is less than 20%, packed erythrocyte transfusions are administered
- Prevent circulatory overload and pulmonary edema from ventricular failure.
Postpartum Management
- Early ambulation to prevent venous thrombosis
- Adequate hydration
- Analgesic drugs should be given for pain relief
- Cord blood should be sent for electrophoresis.
Contraception
Progesterone based contraception like depot medroxyprogestrone acetate is safe and has beneficial effect of decreasing sickling due to stabilization of erythrocyte membrane. Barrier method is widely used but rate of failure is high. Permanent method is advised on completion of family.
Thalassemia
There are many point mutations in the globin gene that may cause beta thalassemia minor, and this explains the clinical variability of the condition.33 This anemia is microcytic and hypochromic, and there is basophilic stippling of the erythrocytes. The hemoglobin levels range from 8 to 10 g/dl. The diagnosis is frequently missed, and the patients are repeatedly treated with large doses of oral, and in some instances, parenteral iron without therapeutic response. This is dangerous because they may develop hepatic and cardiac hemosiderosis secondary to iron overload.
The diagnosis of beta thalassemia minor should be suspected when the MCV is 75 fl or less and the RBC is greater than 4.5—5.0 million cells/μL. If still doubtful, measurements of serum ferritin and serum iron will clarify the dilemma. Also, microcytic, hypochromic anemia which does not respond to oral iron by an elevation of her hemoglobin concentration after 4 weeks of treatment should raise suspicion of thalassemia. Patients with beta thalassemia minor characteristically show hemoglobin A2 (HbA2) concentrations greater than 3.5% and normal or increased serum iron concentrations. In 90% of the cases, the HbA2 level is above 5%. Approximately 50% of women with beta thalassemia minor will exhibit a hemoglobin F concentration greater than 2%.25
Immune Hemolytic Anemia
In immune hemolytic anemia, the patient makes autoantibodies of the immunoglobulin (lgG) type or “warm antibodies” against red cell antigens, causing premature destruction of these cells. In other cases the RBCs are sensitized with both an IgG antibody and complement, usually C3. More rarely, the RBCs only exhibit complement and no IgG. This abnormality may occur in association with several diseases (leukemia, lymphomas, viral infections) or as a consequence of an immune reaction to certain drugs (penicillin, sulfas, quinidine). The most frequent cause of this abnormality in pregnant women is an autoimmune disorder. On a few occasions, no cause can be discovered and the disorder is named “idiopathic immune hemolytic anemia.”
The diagnosis of immune hemolytic anemia is made with the direct Coombs test. In this test, red cells of the patient are mixed with Coombs anti-human globulin antiserum, and since they are coated with IgG and complement, agglutination occurs immediately.
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