Our goal...

Eradicating anemia for safer motherhood & healthier generations

Bangalore Society of Obstetrics & Gynaecology www.bsog.in

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BANGALORE SOCIETY OF OBSTETRICS AND GYNAECOLOGY

TEAM BSOG 2007- 2008

Office bearers: President: Hon. Secretary: Hon. Treasurer: Vice President: President Elect: Hon. Joint Secretary: Dr. Arulmozhi Ramarajan Dr. Harsha N Biliangady Dr. Parvati Javali Dr. Reeta H Biliangady Dr. Susheela Rani B S Dr. Jyothika A Desai

Executive Committee: Dr. Chandrika M Dr. Jayanthi T Dr. Malini K V Dr. Parimala Devi Dr. Venkatesh N Dr. Devika Gunasheela Dr. Lata Venkataram Dr. Nagarathnamma Dr. Swetha Arasu Dr. Vidya Bhat

Invited members: Dr. Kamini A Rao Dr. Hema Divakar Co-opted members: Dr. Prakash K Mehta Dr. Sheela V Mane Dr. Sita Bhateja Dr. Sunanda Kulkarni Dr. Vaijayanthi N V

We can make a difference

In our population, anemia appears to be the rule rather than the exception. No age seems to be exempt. It cuts lives short. It runs as an undercurrent in many premature deaths. It brings down an individual's productivity and thereby affects the nation's economy. Most importantly, it is largely preventable & easily treatable. This is where we can make a difference. By preventing, treating anemia in one woman, we will be giving that family a healthy mother who will be pivotal in raising a healthy and happy family. This monograph on anemia is to help understand the ailment better, to help eradicate it from our society. It is a small effort to put together important aspects of the disease, its causes, presentation, diagnosis and management, in a simple fashion to make it a ready reference for the practicing Obstetricians, Gynecologists and family physicians. Eminent practitioners and senior teachers have contributed chapters in this monograph. The pages take us through an overview of the problem, a historical note, its presentation through the different stages in life, the types of anemia, investigations and management. A write up on the judicious use of blood and blood products adds color to the book. The case reports from our own members give a personal and clinical touch to the issue. I express my deep sense of gratitude to all the authors, who have taken precious time off to add value to the book. My special thanks are due to Dr. Pankaj Desai and Dr. Kamini A Rao for their forewords and words of encouragement. I am grateful to my friends Dr. Prakash K Mehta and Dr. Susheela Rani B S for their help in structuring and editing. I express my sincere thanks to Dr. Reddy's Labs for bringing out this book.

Dr. Arulmozhi Ramarajan President, BSOG 2007-08

FOREWORD

Anemia seems to haunt Indians since mythological days. Pandu the patriarch of the Pandavas was believed to be suffering from this condition. Traditionally we have been defining anemia as hemoglobin less than 10 gms%. However, time may have come to review this definition as we Indians seem to be comfortable at a shade lower of hemoglobin levels. This is not to dilute the efforts of anemia eradication but putting a poser to research scientists on this matter. Do we Indian have a tendency to have lower hemoglobin? Well as of now it is anybody's guess. Obstetrics they say is a "bloody" business. Having to face hemorrhage when the mother is already anemic is like pushing her over the brink from the edge. The traditional definition of hemorrhage pegging the amount of blood loss at > 500 ml too goes for a toss when you see it in the light of an anemic mother. Therefore Indian obstetricians wisely define hemorrhage clinically rather than waiting for the blood loss to go upto 500 ml. In anemic subjects this could be lethal. Understandably, nutritional causes remain in focus in most discussions on anemia. However in India there are vast belts where non-nutritional anemia too has a firm grip in form of sickle cell anemia or Thalassemia. Interestingly the distribution of Thalassemia throughout the world explains mysteries of movements of land masses. The way Thalassemia occurrence is distributed, it shows that Australia and its nearby areas including Fiji, Papua New Guinea and New Zealand where all one land mass with Asia. Seismologicaly now thought to be the most stable part of the earth Australia, was separated from Asia ironically through an earthquake carrying along the genes of Thalassemia. Thus anemia is not only of interest to doctors but also to geologists! What was a very popular route of iron administration: I.V. Total dose Iron administration has thankfully lost its popularity of the 80s. It was very hazardous and life endangering which looking at the risk-benefit ratio was untenable. It is also interesting to know that any oral iron preparation if does not produce some amount of gastric side effects, is ineffective. Thus when a pharmaceutical company tries to sell you an iron preparation with no gastric side-effects, rest assured it is also ineffective!

FOGSI philosophy for 2007 is FOGSI Cares 2007. In this FOGSI also cares for anemic adolescents. So as to catch them young: we at FOGSI are focusing on identification of anemic young girls so that by the time they approach motherhood they are no more anemic. In this it will be pertinent to state that one more point where anemic motherhood can be averted is by treating anemia in women who come for infertility treatment. This is a point where before treating her infertility we can make her non-anemic so that when she is safe on this count from dangers in child bearing. I commend Bangalore O & G society for taking up this theme in a big way.

Dr. Pankaj Desai President Federation of Obstetric & Gynecological societies of India

FOREWORD

Anaemia is a major public health hazard in India affecting all segments of the population in general and children, women and pregnant women in particular. It is the single most important cause of maternal morbidity and mortality contributing directly to 20% of maternal deaths and indirectly to a further 20%. What is doubly distressing is that the most common cause of anaemia in India is nutritional anaemia. Nutritional deprivation compounded by chronic blood loss due to hookworm and malarial infestations as well as poor bio availability further enhances the incidence and severity of anaemia. In an era of hope kindled by awesome scientific advances, we in India are still battling with the paradox of high maternal morbidity and mortality - much of it due to anaemia. Reducing the burden of anaemia is essential to achieve the WHO's Millennium Development Goals relating to maternal and childhood mortality. According to WHO, the strategy for control of anaemia includes detection and appropriate management; prophylaxis against parasitic diseases and supplementation with iron and folic acid; and improved obstetric care and management of women with severe anaemia. Successful delivery of these cost effective interventions requires the integrated efforts of several health programs particularly those targeted at pregnant women and young children and the strengthening of health systems, increased community awareness and financial investment on the part of the government. Creating awareness about anaemia should be a major 'thrust issue' for each and every member of the medical fraternity and this book aims to do just that. This Monograph covers each and every aspect of the detection, management and prophylaxis of the various types of anaemia. The book has been written in a lucid language with extensive diagrams, photographs and flow charts to give clarity to the subject. I must congratulate Dr. Arulmozhi Ramarajan on this superlative effort which I am sure will soon be an essential not only for physicians but also for medical students, obstetricians, nurses as well as the paramedical fraternity. Dr. Kamini A. Rao FOGSI Representative to FIGO Director, Bangalore Assisted Conception Centre

Eradicationg Anemia: Reaching the Unreached

"It is from numberless diverse acts of courage and belief that human history is shaped. Each time a man stands up for an ideal, or acts to improve the lot of others, or strikes out against injustice, he sends forth a tiny ripple of hope, and crossing each other from a million different centers of energy and daring those ripples build a current which can sweep down the mightiest walls of oppression and injustice." - Robert F. Kennedy -

SCIENTIFIC SECTION
CONTENTS 1. Anemia: Issues & Interventions 2. Anemia through the ages 3. 4. 5. 6. 7. 8. 9. Fetal anemias Childhood anemia Anemia in adolescence Bolt from the blue: Anemia of acute blood loss Off color @ forty plus Hereditary anemias Acquired hemolytic anemias Dr. Arulmozhi Ramarajan Dr. Malathi Rao Dr. Ramamurthy B S Dr. Christi D Savio Dr. Sheela V Mane Dr. Prakash K Mehta Dr. Devika Gunasheela Dr. Hema Divakar Dr. Biliangady Harsha N Dr. Narayanan Dr. Latha Venkataram Dr. Jayanthy T Dr. Jyothika A Desai Dr. Sita Bhateja Dr. Susheela Rani B S Dr. Biliangady Reeta H Dr. Shivaram Dr. Malini K V Dr. Swetha Arasu & Dr. Teena Thomas

10. Thalassemia in pregnancy 11. Uncommon causes of anemia 12. Investigations: What, when & why? 13. IDA in pregnancy 14. Eating right right from now! 15. Mirror, mirror on the wall. 16. Refractory anemia in pregnancy 17. Hemotherapy in ObG: When, why & how? 18. Anemia in pregnancy - a teaching hospital experience 19. Blood banks in Bangalore

20. Case reports

ANEMIA: ISSUES & INTERVENTIONS

Dr. Arulmozhi Ramarajan, MBBS, MD, DGO, PGDMLE Consultant and Head of ObGyn Church of South India Hospital, Bangalore

INTRODUCTION:
Anemia is one of the world's most widespread health problems. It affects more than 2 billion people worldwide, women and children being more affected. The word anemia in Greek means "without blood." It is the generic name given to a group of disorders characterized by a quantitative or qualitative deficiency of the circulating erythrocytes. In India, about 52% of the women of reproductive age & 74% of children are anemic. In a 2002 report, WHO lists iron deficiency, a major cause of anemia, as one of the top 10 risk factors in developing countries, for lost years of healthy life. Conservative estimates suggest anemia is the direct cause of 3 to 7 percent of maternal deaths worldwide. Other estimates suggest it is the direct or indirect cause of 20 to 40 percent of maternal deaths. Reducing the number of women dying in childbirth by 3/4ths by 2015 is one of the key goals of the Millennium Declaration of the World Health Organization. This goal was agreed upon by world leaders from 189 countries at the UN Millennium Summit in September 2000. If we should bring down our maternal mortality and morbidity, we need to tackle anemia on a war footing.

Anemia Prevalence (WHO) Age group Children 0 - 4 years Children 5 - 14 years Pregnant women Women 15 - 59 years Men 15 - 59 years Elderly > 60 years Industrialized Countries 20.1% 05.9% 22.7% 10.3% 04.3% 12.0%

Non Industrialized Countries

39.0% 48.1% 52.0% 42.3% 30.0% 45.2%

Causes of Maternal Death and contribution of 3 Iron Deficiency Anemia (IDA)

Other Direct Causes 5%

Unclassified 6%

Anemia 8%

HIV 3%

Deaths Associated with IDA 22%

Indirect Causes 14%

Hemorrhage 31%

Obstructed Labor 7%

Sepsis 11%
Unsafe Abortion 5%

Hypertensive Disorder 10%

Adapted from Khan et al, Lancet April 1 2006

ISSUES:
Anemia has serious negative consequences including increased mortality in women and children, decreased capacity to learn, and reduced productivity in all individuals. Its devastating effects on health, physical and mental productivity affect the quality of life and translate into significant economic losses. Women are vulnerable to malnutrition and anemia throughout their life cycle for both biological and social reasons. Anemia begets anemia. At birth, the hemoglobin level and iron stores depend upon the nutrient inputs from the mother. A normal weight, full term infant that is born to a healthy mother and gets exclusively breastfed manages enough iron from its own stores and from breast milk. The stored iron is exhausted in about six months. Additional iron is then required because the iron content of unfortified conventional complementary foods is insufficient to meet the high iron requirements of growing 6 to 24 months old infants and children. Infants and children who do not obtain adequate iron will suffer cognitive impairment that will affect their ability to learn and to perform income earning tasks later in life. The sad part is that subsequent supplementation of iron cannot correct the cognitive impairment. Many of the girls who survive under such nutritional stress are stunted, with little chance of recovery. Anemic children are apathetic and anorexic, do not have energy to play, and have trouble learning. In societies with gender discrimination, girls face greater degrees of deprivation in food, education and opportunities to bring out their best. Adolescence is a period of rapid growth, and the requirements for iron are high. Adolescents are particularly vulnerable to anemia caused by multiple nutritional deficiencies and helminth infections. This increased requirement of iron continues throughout the reproductive years because of menstrual blood loss, the iron demands of the developing fetus, and blood loss during delivery. Teenage pregnancy is like adding fuel to fire. Anemia in the growing years makes these
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children more susceptible to infections including tuberculosis, malaria and HIV. Through the reproductive years, women in developing countries are pregnant, lactating or pregnant and lactating. If they do have a break, it is highly likely that they have abnormal blood loss during menses. Anemia is the rule rather than exception. Physical work capacity and fitness are reduced in anemic women because iron is needed by the blood to carry oxygen to the brain and muscles and by the muscles for normal functioning. Anemic women are more likely to deliver low birth weight infants. They transfer less iron to their fetuses. And these infants are at increased risk of becoming iron-depleted in early infancy. Anemic women are more susceptible to puerperal sepsis. Women with severe anemia are particularly at risk and have a 3.5 times greater chance of dying from obstetric complications than women who do not have anemia. Anemia related fatigue also makes the effort of labor more difficult, thus prolonging labor. Severe anemia can lead to heart failure at the time of labor and delivery. Although it is currently accepted that only severe anemia causes maternal mortality, it has been estimated that moderate anemia increases a woman's chance of dying 1.35 times, making it a risk for maternal mortality. Many more women have mild to moderate anemia than severe anemia. This emphasizes the importance of preventing and treating all forms of anemia, as the number of deaths associated with mild to moderate anemia is potentially greater than the number associated with severe anemia. Various factors including lack of knowledge and awareness, cultural taboos, incorrect food practices, infections and infestations, lack of access to services and poverty have contributed to the continued prevalence of this much treatable disease. Anemia is frequently multifactorial. While iron deficiency is the most common cause of anemia worldwide, genetic traits, such as thalassemia and hemoglobinopathy (eg, sickle cell disease, glucose-6-phosphate dehydrogenase deficiency, hemoglobin E disorder) should also be considered in people of Southeast Asian, African, and Mediterranean descent. In cases of anemia unresponsive to treatment with iron supplementation, hemoglobin electrophoresis should be performed once iron stores have been replenished. Recognition, correct classification (diagnosis) and treatment are of the utmost importance in the management of anemia.

INTERVENTIONS:
History has it that the Greek physicians equated iron with strength and treated weakness in patients with water in which old swords had been left to rust. In the 17th century, Thomas Sydenham used iron and steel filings steeped in Rhenish wine for the treatment of chlorosis, an old name for iron deficiency anemia. We are certainly better placed today, when it comes to interventions to eradicate anemia. The methods are inexpensive and effective. As primary care physicians for women, Obstetricians
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have the means, the potential and a duty to achieve this goal of eradicating anemia. We can make our women and children stronger and healthier, and this in turn will reflect in the overall growth and development of the country.

Here's how we can contribute:

General measures:
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Health education to create and enhance anemia-awareness amongst our women, children and health workers. Malaria and hookworm prevention and treatment particularly in endemic areas. Periodic iron and folic acid supplementation (60mg of iron and 400g folic acid for 3 months) for prepubertal and adolescent girls and for all women of childbearing age, in areas of high prevalence of anemia. Certain drugs can cause megaloblastic anemia. Diphenyl hydantoin, barbiturates and oral contraceptive agents interfere with folate absorption, and metformin that is widely used in treating DM and PCOS interferes with B12 absorption. Those on long term therapy with these drugs must be closely monitored.

v v

In infancy & childhood:

v

Delayed cord clamping in newborns has shown to increase their iron stores. However, caution should be exercised in Rh Negative pregnancies, for fear of Rh isoimmunization and risk of hemolysis in the neonate. Exclusive breastfeeding from within one hour of birth to at least six months of age. Avoidance of prelacteal feeds is equally important. Inculcating good eating habits from a tender age is important. Introducing fortified foods is an effective way of preventing and treating deficiency disorders. Iron Folic Acid supplements & deworming for school children. Ensuring basic education to the girl child and empowering her for the life ahead.

v v v v

In pregnancy:
v

Providing at least 100mgs of iron for 100 days during pregnancy and continuing the same for at least three months after delivery.
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Routinely deworming pregnant women in the second or third trimester, or in the post partum period. This should become as routine as giving tetanus toxoid, and is sure to reap bigger benefits. Making deliveries safer, by reducing blood loss during delivery. Active management of the third stage, use of prophylactic ergometrine / oxytocin / carboprost and taking care to avoid traumatic deliveries are direct ways in which we can contribute to improved outcomes. Providing safe blood transfusions for women with severe anemia is extremely important and life saving. In situations where a requirement for transfusion is anticipated, for example in placenta previa / previous cesarean section / severe anemia / HELLP syndrome, one needs to be adequately prepared.

In the post partum period:

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Encouraging exclusive breast feeding. This minimizes postpartum bleeding when initiated within an hour of delivery. Additional benefits include lactational amenorrhoea which is a saving on menstrual loss. It also contributes to a delay in the return of fertility. Thus even if the woman has not accepted any specific contraceptive method, she is less likely to become pregnant during lactation, and less likely to come asking for a termination of pregnancy. For those who accept oral contraceptive pills, taking IFA tablets during the blank weeks should be emphasized. Injectable progesterone contraception should be promoted, for the added benefit of amenorrhoea during its period of use. Monitoring blood loss in IUCD users is important. It is imperative to advise use of antifibrinolytic / other styptic medication to reduce blood loss in the initial menstrual cycles.

Little drops of water make a mighty ocean, goes the saying. Let every mother and child count. Let's do our bit to paint our nation pink.

References:
WHO Fact Sheet No. 276 / Feb 2004. Khan et al. Lancet April 2006. WHO The World Health Report: Reducing risks, promoting healthy life. Geneva, 2002. Khanal P, Walgate R. Nepal deworming program ready to go worldwide. WHO Bulletin, 2002, 80: 423-424.
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National family Health Survey-India (NFHS-II) 1998-99, International Institute of Population Sciences. Demographic Health Survey, 2000. Survival for Women and Children (SWACH) Foundation. 1997. Anemia in Pregnant Women and Adolescent Girls in Rural Areas of Haryana, India. Quarterly Progress Report: April to June 1997. Awasthi S et al. Effectiveness and cost effectiveness of albendazole in improving nutritional status of preschool children in urban slums Indian Pediatrics 2000, 37, 19-29. Concise hematology by H J Woodliff. Allen LH (2000) Anemia & Iron Deficiency: Effects on pregnancy outcome. Am. J of clinical nutrition 71: 1280S 1284S. Barbin B J, M Hakimi, D Pelletier (2001) An analysis of anemia & pregnancy related maternal mortality. J of nutrition 131: 604S 615S. Mahomed K (2000) Iron supplementation in pregnancy (Cochrane Review) in The Cochrane Library, Issue 3, Oxford Update Software.

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Anemia through the ages

Dr. Malathi Rao MBBS. FRCS. FACOG Manipal North side Hospital Bangalore

What is Anemia? Anemia is a blood disorder characterized by abnormally low level of RBC in the body. It is usually a sign of underlying disease. Historical perspective: Ancients recognized blood as life giving substance. Hebrews in patriarchal age maintained that blood was the seat of the soul. In Mosaic Law blood is drained before an animal was prepared as food (practice still followed by Jews). Circulation of blood was stated by William Harvey in seventeeth century. 1637 80 Jan Swammerdam discovered what he called as Ruddy globules by looking at blood through microscope (obviously RBC). 1739 74 William Hewson who published his opinion posthumously that red cells were present in such numbers, they have to be important. This earned him the title of Father of Hematology. In 19th century Anemia the word was used clinically to refer to pallor of skin, mucous membrane etc. 1891 Ehrlich developed triacd stain which allowed him to classify WBC into a scheme similar to the one we use today. 1905 Gritav Giemsa found the giemsa stain and in 1906 J.H. Wright found wright stain, both of which are in use routinely in clinical laboratories. Era of modern Hematology is considered to have begun at Harvard Medical School with the work of George Richards Minot and his assistant William Parry Murphy. In 20th century Hematologists are able to diagnose, classify anemia easier, faster, and cheaper and techniques are developed for treating them from simple nutritional and drug therapy to advanced modalities like blood transfusion, bone marrow transplants and recently with stem cell therapy. From this point the investigation of Anemia revolved around the molecular level.

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Anemia Causes And Types Sickle cell A A of acute blood loss Fanconi' A Hemolytic A Inherited - Hereditary Sphrocytosis Enzymatic pyruvate kinase G6PD deficiency Acquired - Drugs, Auto immune, physical Agents, Micro angiopathic HA, Paroxysmal nocturnal hemoglobin urea Iron deficiency A Megaloblastic A. Vit B 12 , Folic acid Pernicious A. 80%, Post surgery, Non megaloblastic macrocytosis Common Causes

Thalassemia Sideroblastic A Aplastic A.

Anemia of chronic diseases

Cancer

Chronic Inflammation

AIDS

Liver Disease

Kidney Failure

Iron deficiency Anemia (IDA)

History: A disease believed to be IDA is described in about 1500 BC in the Egyptian Ebers Papyrus. It was termed Chlorosis or green sickness in Medieval Europe and iron salts were used for treatment in France by mid 17th century. Thomas Sydenham recommended iron salts as treatment for chlorosis but treatment with iron was controversial until 20th century, when its mechanism of action was more fully elucidated. Current concepts: IDA is the most common form of malnutrition in the world and is the eight leading cause of disease in girls and women in developing world. IDA is highly prevalent among women of reproductive age in south East Asia 50-70%, but the prevalence in pregnant women remains at 63.5%. Impact on pregnancy: Problem of under nutrition in India generally starts much earlier in life with gender discrimination, menstrual loss, and socio economic status, multiparity, and late or no ANC.Even interventions like reducing fertility and iron supplementation during pregnancy will have beneficial effect but still leave most women iron deficient. Effects on pregnancy Increased preterm labor, a 2.6 fold increase in PPH and a 3.1 fold increase in low birth weight babies. All pregnant women should receive prenatal care along with adequate iron supplementations to decrease the poor outcome in pregnancy.

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Megaloblastic Anemia
History: 1880 -Ehrlich distinguished between cells he termed megaloblasts in the blood in Pernicious anemia from normoblasts. 1887 Quinckle reported large and irregular red cells. 1921 Zadek noted megaloblasts in the marrow in real life. 1923 Naegeti described hyper-segmented netrophils in peripheral blood in PA. 1932 Tempka and Braun described metamyelocytes in the marrow. 1878 1976 George Hoyt whipple studied the rate of hemoglobin regeneration in dogs made anaemic by venesection. 1885 1950 George Richard Minot and William Murphy isolated the curative substance as vitamin B 12. All three shared Nobel Prize in Medicine in 1934. Causes of Megaloblastic Anemia: 1. Pernicious anemia 80% 2. Post surgery gastrectomy and Ileal resection 3. Bacterial overgrowth, parasitic infection 4. Drug therapy 5. Erythroleukemia 6. Hereditary disorders Causes of Non Megaloblastic anemia: Macrocytosis usually asymptomatic but when associated with anemia cause wide variety of symptoms. 1.Alcohol abuse and liver disease. 2. Hypothyroidism. 3. Reticulocytosis. 4. Aplastic anaemia 5. Paroxysmal nocturnal haemoglobinurea. Current concepts: Megaloblastic anemia is always associated with folate and vitamin B12 deficiency. Caused by slowing of DNA synthesis in all proliferating cells but most apparent in rapidly growing cells such as haematopoietic precursors. RNA synthesis proceeds normally leading to larger proportion of cytoplasm compared to the nucleus resulting in megaloblasts. Etiology of impaired DNA synthesis is due to thymidylase synthetase deficiency because of low folate and vitamin B12, which reduces tetrahydrofolic acid responsible for thymidylate production. Impact on Pregnancy: MA in pregnancy is usually secondary to folate deficiency. Diagnosed in third trimester or postpartum period because of the adequate storage of folate for upto 20weeks, which is utilized before anemia becomes apparent.
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Initially increased incidence of spontaneous abortion, abruption placenta and third trimester bleeding has been reported. However other studies have failed to confirm these findings. IUGR has been attributed to folate deficiency but is probably due to inadequate placentation. Embryopathies such as neural tube defects are associated with folate deficiency and supplementation with folic acid before and in early pregnancy reduces the incidence. Preventive dose of Folic acid -- 5 mg / day 3 months before pregnancy Supplementation dose of Folic acid 4mg / day 3 months before pregnancy Minimal requirements of vitamin B12 are necessary for adequate fetal development and serum B12 levels are usually higher in infants than their mothers accounting for lack of significant deleterious effects on fetus in mothers with PA. Some have described deficiency syndrome in breast fed neonates of mothers with B12 deficiency characterized by failure to thrive, developmental regression, and anemia apparent at 6 moments of age.

Sickle cell anemia

Sickle cell anemia is the first genetic disorder whose molecular basis was identified. History: Known to the people of Africa for hundred of years. 1910 James B Henick noted sickle shaped RBC in a patient from West Indies. 1922 Vernon Mason named the disease as sickle cell disease. 1927 Hahn and Gilespie showed sickling of RBC was related to low oxygen tension. 1940 Sherman, a student from John Hopkins noted low oxygen altered the structure of Hemoglobin. 1948 Jenet Watson showed paucity of sickle cells in peripheral blood of newborn and stated that it was due to fetal hemoglobin. 1956 Vernon Ingram and J.A. Hurst sequenced sickle cell hemoglobin and identified glutamic acid at position 6 was replaced by valine thus diagnosing the molecular basis of the disease. 1995 Hydroxyurea the first and only drug proven to prevent complications of the disease was reported by multicentric study. 1984 The first bone marrow transplant in a child with sickle cell disease was reported and the cure of the disease was published. Current concepts: Sickle cell syndromes are autosomal recessive inherited disorders that result from production of structurally abnormal chain of adult hemoglobin molecule. Hemoglobin S the defect occurs at 6th position of chain where valine is substituted for glutamic acid. Hemoglobin C lysine is substituted for glutamic acid at 6th position. Impact on pregnancy: Exacerbations of disease. Vaso occlusive crisis more common. More prone to pyelonephritis.
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Predisposes to symptomatic cholelitheasis and preeclampsia. Increase in maternal and fetal mortality and morbidity. Before 1970 fetal loss rate was 80% and maternal mortality was 30 40% Today maternal mortality reduced to less than 1% with aggressive prenatal care, effective management and intervention in pregnancy.

Hemolytic anemia
History: 1871 Vanlair and Massius first described Hereditary Spherocytosis. Current concepts: Hemolytic anemia ( HA) is characterized by an increased rate of erythrocyte destruction. This premature destruction occurs due to 2 causes 1. Intrinsic defect Inherited disorders and require molecular diagnosis. a. Hereditary Spherocytosis Inherited as autosomal dominant transfer and occurs due to anomaly of RBC membrane. b. Enzymatic defect i. Pyruvate Kinase Deficiency. Mutation involves structural gene coding for L type pyruvate kinase.( Embden Meyerhoff pathway) ii. G6PD deficiency (Phosphate pathway). X linked disorder. Fully expressed in heterozygous males. In females enzyme activity may be normal, moderately reduced or deficient. 2. Acquired HA. : a. Micro angiopathic hemolytic anemia. Preeclampsia, HELLP syndrome, HUS. b. Paroxysmal nocturnal haemoglobinuria. c. Auto immune hemolytic anemia. d. Physical agents thermal injury, physical agents like prosthetic valves, drugs. Impact on pregnancy: Hereditary spherocytosis in pregnancy is rare. Aplastic or hemolytic crisis may be the first manifestation of the disease in pregnancy. Folic acid requirements are increased. When fetus is affected with hereditary spherocytosis jaundice may be more prominent in newborn, requiring exchange transfusion. Pyruvate kinase deficiency Limited data is available in literature but well tolerated in pregnancy. In the fetus it can cause NON IMMUNE HYDROPS. G6PD deficiency Variable effects in pregnancy. Increased incidence of spontaneous abortion, stillbirth, LBW, neonatal jaundice, and non immune hydrops are reported.

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Aplastic Anemia
Current concepts: Etiology is unknown in many cases. Rare and acquired disease usually due to bone marrow failure secondary to physical, chemical, infectious insults, or nutritional deficiency. Diagnosis depends on laboratory evaluation, bone marrow biopsy and peripheral blood examination. Introduction of bone marrow transplant as treatment in1969 by Thomas et all have changed the life expectancy of these patients.30 years ago 1in 10 patients survived for 1 year and now 7 out of 10 survive and are restored to a quality of life.

Thalassemia in pregnancy
Current concepts: Thalassemia syndromes are inherited disorders that result from decreased synthesis of or globin chain leading to reduced hemoglobin concentration. Impact on pregnancy: Women with Thalassemia major both and rarely live to become pregnant. Obstetric focus is prenatal diagnosis and recognition of carrier state in couples. Prenatal diagnosis is possible by obtaining fetal cells for DNA analysis. Replacement of blood and blood components in obstetrics. Storage and transfusion of sterile compatible blood or blood constituents is a routine and life saving procedure in obstetrics. Key developments: 200AD Reports of mystical qualities of blood is noted. 1667 - Richard Lower reported first heterologous blood transfusion from lamb to an insane man. 1818- James Blundell initiated first human-to-human blood transfusion in acute hemorrhage due to PPH. 1900 Karl Landsteiner defined the blood groups and donor and recipient could be precisely matched. 1914 Hustin added citrate to prevent clotting. 1937 First blood bank was established in Cook county hospital, U.S.A. Bone marrow transfusion: Century ago bone marrow was administered by mouth to patients with anemia and leukemia. 1950 Early attempts were made with several transplants in France following radiation accident. 1958 Jean Dausset described human histocompatibility antigens. 1968 First successful Bone marrow transplant was done at the university of Minnesota, U.S.A. The recipient was a child with severe combined Immunodeficiency and the donor was a sibling. 1973 Physicians at Sloane Kettering cancer institute N.Y. performed unrelated bone marrow
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transplant in-patient with Combined Immune deficiency syndrome and after 7th time engraftment was achieved and hematological function became normal 1970 First patient with acute Leukemia was treated with unrelated bone marrow transplant with success. 1980 Various individual registries of HLA typed people were established. 1986 national bone marrow donor registry began operations in U.S.A. 1990 Dr. E. Donnall Thomas was awarded the Nobel Prize in Medicine for his pioneer work in transplantation. Today Bone marrow transplant is used in many hematological diseases notably in Leukemia and Aplastic Anemia. Stem cell therapy: Several types of stem cells have been discovered from germ cells, the embryo, fetus, and adults. Each of these has the potential to revolutionaries the future of regenerative Medicine in cell replacement therapy and to treat a variety of debilitating diseases. Stem cell is a cell with the ability to divide indefinitely in culture and with the potential to give rise to mature specialized cell types. Stem cells can be embryonic origin or adult stem cells found in diverse tissues and organs. The best-studied adult stem cell is the haematopoietic stem cell ( HSC), which have been used in clinical settings for over 40 years and form the basis of Bone marrow transplant success. Umbilical cord blood contains a rich source of HSC that can be used to reconstitute the blood system and can easily be extracted and cryopreserved, thus allowing HLA typed stem cell banks to be established. Marrow and Cord blood transplantation technology continue to evolve and has the potential for use in Medical therapy of numerous life threatening diseases. References: Medline search Clinical Obstetrics and Gynecology- September 1995, volume 38, number 3 Williams Obstetrics

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Foetal Anaemia
Dr. B.S.Rama Murthy MD DMRD DNB Consultant Radiologist, Srinivasa Ultrasound Scanning Centre Bangalore

Anaemia is defined as a pathological deficiency of the oxygen carrying component of blood measured in unit volume concentration of Haemoglobin (Hb), red blood cell volume or red blood cell number.

Foetal haemoglobin concentration increases with gestational age (GA). Hence the threshold Hb concentration value below which foetal anaemia exists varies with gestational age. Multiples of median enable us to express the level of Hb concentration below which foetal anaemia is diagnosed.
18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 16 18
1.16 Median 0.84 Mild anemia Moderate anemia Severe anemia

0.65 0.55

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22

24

26

28

30

32

34

36

Gestational Age (Weeks)

Mari G and the group of sixteen others classified foetal anaemia as follows: Mild anaemia Hb conc. 0.84 to 0.65 the median for GA Moderate anaemia Hb conc. 0.65 to 0.55 median for GA Severe anaemia Hb conc. less than 0.55 median for GA Hydrops occurs when the Hb concentration falls below 5 gm/dl which corresponds to 0.46 times the median at 18 weeks and 0.36 times the median at 37 weeks. Foetal anaemia is caused either by decreased production or increased destruction/loss of red blood cells. Decreased production: Congenital eg. Fanconi's pancytopenia, TAR syndrome, Diamond Blackfan anaemia congenital dyserythropoietic anaemia etc. (marrow hypoplasia syndromes).
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Acquired such as parvovirus B 19 infection. Increased destruction/loss: Alloimmune anaemia (D, Kell, Kidd, ABO incompatibility), foetomaternal haemorrhage, donor foetus in twin to twin transfusion sequence. Haemoglobinopathies which affect the oxygen carrying capacity in the foetus may also be considered. Alphao thalassemia (Bart's Hb) is an example and results in early foetal hydrops. In anaemic fetuses the change in haematocrit results in a change in the blood viscosity and in turn results in impaired release of oxygen to the tissues. Increased cardiac output and vasodilatation are the main mechanisms by which the foetus attempts to keep metabolic equilibrium.

Diagnosis:
Obstetric history: Blood group and Rh type of mother and father, anti D administration in previous pregnancies or abortions, previous issues with specific syndromes It is the history that puts the process of foetal investigation underway. Sometimes ultrasound detected foetal hydrops may set forth the process of investigation. Maternal investigation: Relevant maternal investigations include Anti red cell antibody titre (titres greater than 1 in 16 may prompt foetal testing however it should be pointed out that the Indirect Coomb's test titres may not correlate with foetal haemoglobin levels), TORCH and Parvovirus molecular or immunologic testing, Kleihauer Betke testing to recognize and quantitate foetomaternal haemorrhage. Foetal non invasive investigation: Ultrasonography: Includes grey scale and doppler imaging Grey scale imaging: = Foetal hepatosplenomegaly reflects extramedullary erythropoiesis. Spleen length and perimeter nomograms help us in objectifying the diagnosis. = Small bowel serosal definition reflects presence of very early ascites. = Bobbing cord sign reflects hyperdynamic circulation. = Hydrops foetalis end result of severe anaemia is severe tissue hypoxia / acidemia, cardiac failure and decreased plasma oncotic pressure. = Placental thickening, polyhydramnios, Doppler imaging: Decreasing Hb levels are associated with rising velocities in foetal circulation. This relation has been proved in several series. High cardiac output and reduced blood viscosity are the factors which result in hyperdynamic vascular flow states. Initially intrahepatic umbilical vein and ductus venosus velocities were studied. We now have a large body of convincing evidence showing that decreasing Hb concentrations are linearly related to increasing MCA peak systolic velocities (PSV). MCA has been the chosen vessel because of the ease with which it can be demonstrated by colour doppler. It's orientation enables one to achieve 0o or as close to 0o
23

doppler angle easily. The point of sampling is just beyond its origin from the internal carotid artery in the plane of circle of Willis. The mapping is done with colour flow. Spectral doppler is run for a few seconds only. The interobserver and intraobserver variability is low. Serial MCA PSV measurements are at weekly intervals beginning from 20 to 22 weeks gestational age. All fetuses with moderate or severe anaemia have PSV's above the 1.5 MoM's (multiples of median) for gestational age. When this level of MCA PSV is reached invasive diagnosis and therapy is planned (cordocentesis and intrauterine transfusion). Foetuses with below 1.5 MoM's MCA PSV have no anaemia or mild anaemia (which anyway does not need transfusion). The 1.5 MoM cut off has a sensitivity of 88% and specificity of 87% for moderate to severe anaemia. With the advent of MCA PSV surveillance amniotic fluid spectrophotometry is almost totally given up. Amniocentesis and Liley curve has a sensitivity of 76%. The correlation between foetal Hct and MCA PSV is excellent not only for alloimmune anaemia but also for anaemia due to other causes. MCA PSV surveillance has made it possible to avoid 70% of invasive procedures. Furthermore the MCA PSV drops when anaemia is corrected.
100 90 80 70 60 50 40 30 20 10 0 16 18 20 22 24 26 28 30 32 34 36 Median 1.50 Multiples of the median

Gestational Age (Weeks)

Foetal invasive investigation: Amniocentesis: Spectrophotometry (OD change at 450 nm) Foetal blood sampling: Hb%, Reticulocyte count, Hct, Blood group and Rh type, Direct Coomb's test, Bilirubin levels. Therapy: Congenital causes of marrow failure cannot be treated in the true sense of the term. Causes of foetal anaemia due to acquired causes like alloimmunisation, Parvovirus infection or foetomaternal haemorrhage can be managed by intrauterine transfusion until sufficient foetal
24

maturity is attained. Delivery and neonatal management is then planned. Since intrauterine transfusion (intravenous or intraperitoneal) is the bedrock of treatment we shall now go through a few relevant details. Foetal transfusion is needed in only 10% of at risk fetuses (Rh incompatibility) for severe anaemia before 34 weeks, the remaining 90% have mild or no anaemia and can be managed with MCA PSV surveillance. With widespread usage of anti D, the incidence of moderate and severe foetal anaemia has fallen. Even so alloimmune anaemia due to Rh incompatibility is still the single largest cause. Counselling: The parents should be counseled regarding the process of treatment, the number of sittings that may be needed and the need for weekly monitoring of MCA PSV post procedure. The possible complications during foetal transfusions should be highlighted. Informed consent is taken. Indication: Moderate / severe foetal anaemia as defined by the nomogram referred to above. Foetal hydrops has lower salvage rates. Preparation: The probe is sterile draped, the abdomen is surgically prepared and draped. No maternal premedication is needed. Tocolysis and antibiotics are started on the morning of the transfusion. Site of foetal access: The cord insertion into the placenta is affords good access both for blood sampling as well as transfusion. The intrahepatic umbilical vein may be used if the foetus is dorsoposterior and the placental insertion site of the cord is difficult to access. Foetal Hb concentration is estimated while the needle is in situ and if anaemia is moderate or severe transfusion is done via the same needle. The pretransfusion foetal blood sample is also subjected to Hct, reticulocyte count, direct Coomb's test and bilirubin estimation. Donor unit: O-ve, packed red cells with a haematocrit of at least 85%, washed and irradiated (100 ml). Cross matching with maternal blood is recommended. Foetal paralysis: Is achieved by Pancuronium 0.25 mg/kg estimated foetal weight injected IM into the foetal thigh. Volume transfused: Is computed using the donor haematocrit, foetal haematocrit and the foetoplacental blood volume for gestational age. Aliquots of 10 ml are injected into the umbilical vein through the needle coupled to a three way. Continuous turbulence is observed in the umbilical vein during the intravenous injection. A check is maintained on the foetal heart rate. At the end of transfusing the desired volume a post procedure foetal blood sample is obtained before withdrawing the needle. Hb, and HCt are obtained. 20 to 30 ml of the donor unit is also transfused into the foetal peritoneum at the end of the intravenous transfusion. Post procedure : Foetal MCA PSV is recorded to demonstrate a drop in velocities. Weekly MCA
25

PSV surveillance is done and the subsequent transfusion is planned when the MCA PSV again reaches beyond 1.5 MoM's. This generally occurs about 2 to 3 weeks after a sitting. Complications: Cord haematoma, foetal exanguination and bradycardia are the complications, Serial transfusions are done until the gestational age is 34 weeks after which delivery is planned. Foetal transfusion is not only done for alloimmune anaemia but also for parvovirus B 19 and foetomaternal haemorrhage as well. The term 'tide over transfusion' is used in these situations. Thus we see that the causes of foetal anaemia are protean. Recognition of foetal anaemia is based on history, maternal and foetal investigations. Foetal transfusions have revolutionized the therapeutic scene. References: 1. Mari G and the collaborative group for diagnosis of fetal anemia with Doppler ultrasonography. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. N Engl J Med 2000;342:914.1. 2. Liley AW. Liquor amnii analysis in the management of pregnancy complicated by rhesus sensitization. Am J Obstet Gynecol 1961;82:135970. 3. Nicolaides KH, Rodeck CH, Mibashan RS, Kemp JR. Have Liley charts outlived their usefulness? Am J Obstet Gynecol 1986;155:904. 4. Fan FC, Chen RYZ, Schuessler GB, Chien S. Effects of hematocrit variations on regional hemodynamics and oxygen transport in the dog. Am J Physiol 1984;238:H54552. 5. Harman CR, Bowman JM, Manning FA, Menticoglou SM. Intrauterine transfusion -intraperitoneal versus intravascular approach: a case-control comparison. Am J Obstet Gynecol 1990;162:1053-1059. 6. Oepkes D, Seward PG, Vandenbussche FPHA, et al. Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 2006;354:156-164.

26

Childhood Anemia
Dr. Christi Dominic Savio MD, DCH, Consultant Pediatrician, Church of South India Hospital, Bangalore

Anemia is one of the commonest problems encountered in pediatric practice with nearly 70 million children below the age of 6 years in our country suffering from it. The vast majority of it is due to the dietary deficiency of iron. This is surprising, given the fact that iron deficiency is eminently amenable to prevention and treatment. What then is the reason for this high prevalence in this day and age? Is it that we doctors are so busy treating other more serious diseases that we forget or ignore this easily remediable condition? Or perhaps we ignore the fact that Iron Deficiency Anemia (IDA) can and does take an enormous toll on the health of the community including causing irreversible and permanent functional damage to the developing brain. This article is an effort to sensitize us to what has been termed the Tragedy of Iron Deficiency Anemia during infancy and early childhood. PRACTICAL DEFINITION OF ANEMIA The normal Hemoglobin varies with the age and sex of the individual and is given in Table 1 below. Anemia is said to be present when the level of Hemoglobin falls below these levels.
TABLE 1: Normal Hemoglobin level
Population Group Adult Male Adult Female (Non pregnant) Adult Female (Pregnant) Children 6 to 59 months of age Children 5 to 11 years of age Children 12 to 14 years of age Source: World Health Organization
4

Normal Hemoglobin (grams per dL) 13 12 11 11 11.5 12

IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA Iron deficiency is the predominant nutritional deficiency that causes anemia all over the world. According to the World Health Organization, iron deficiency is the most common and widespread nutritional deficiency in the world.
5

Relation between Iron Deficiency and Iron Deficiency Anemia Iron deficiency is defined as a condition in which there are no mobilizable iron stores and in which signs of compromised supply of iron to tissues, including the erythron, are noted. It is only
27

Total Population

Iron Deficiency

Iron Deficiency Anemia Anemia

when there is severe iron deficiency that anemia occurs. In mild to moderate iron deficiency tissues are functionally impaired though there is no anemia. It is important to realize that iron deficiency causes impairment of cellular functions even at levels that do not cause anemia Prevalence of Iron Deficiency Anemia (IDA) Iron deficiency is the only micronutrient deficiency that is prevalent in significant numbers in both the developed and the developing countries. WHO estimates that 2.1 billion
6

Venn Diagram showing relationship between Iron Deficiency and Anemia

people globally are affected with anemia mainly because of iron deficiency. This is 30 percent of the total world population! The prevalence of IDA in India based on various studies is as follows
1

TABLE 2: Prevalence of Anemia in various population groups

Population Group Infants and toddlers Children 1 to 6 yrs Adolescent girls Non-pregnant women Pregnant women Lactating women Prevalence (percentage) 65 60
88 (3.3% had severe anemia)

74
85 (9.9% had severe anemia)

56.4

However findings of the DLHS - RCH (District Level Household Survey under Reproductive and Child health programme) jointly done by Ministry of Health and Family Welfare and Department of Women and Child Development in 2002-2003 has put the figures of anemia prevalence much higher as follows TABLE 3: Prevalence of Anemia in various population groups (DLHS RCH Report)
Population Group Children less than 5 years Children 5 to 10 yrs Teenagers 10 to 19 years Prevalence (percentage) 65 92 86
7 7

This is an alarming situation which is worsened by the fact that many among the health profession are blissfully ignorant of the gravity of this problem!

28

Groups at greatest risk for developing IDA are

v v v v v v

Children of all ages, particularly those between the ages of 6 months and 5years Preterm infants Women at the time of puberty, pregnancy and lactation The lower socioeconomic groups Non- meat eating groups Those with diseases like recurrent malaria, hook-worm infestation, and amebiasis.

Consequences of Iron Deficiency It is vital for us to remember that anemia is only one of the consequences (although the most visible one) of iron deficiency. Following are some of the important effects of iron deficiency. 1. Effects on the developing Central Nervous System (CNS) This is one of the most disastrous consequences of Iron deficiency. Iron deficiency results in impaired cognitive performance, diminished IQ, overall decrease in scholastic performance and behavioral abnormalities including Attention Deficit Disorder (ADD). The tragedy of this is that the deleterious effects of iron deficiency on the cognitive performance in infancy and childhood are not correctable by subsequent iron therapy. In other words the impairment in cognitive performance is irreversible. Thus prevention of iron deficiency is the only way to prevent CNS impairments. 2. Effects of Iron Deficiency on Scholastic Achievement in older children Iron deficiency results in poor learning ability even among older children and adolescents. Numerous studies have demonstrated poor learning scores in older children and adolescents with iron deficiency including those with iron deficiency without anemia. 3.
12, 13 8-11

Compromised cardiovascular response to physical exercise The cardiovascular response to physical exercise is compromised in children with nutritional anemia even when it is mild and hence these children may never attain their full potential in various school activities.
14

4.

Impaired Immune Status Iron deficiency causes increased mortality and morbidity from infections in all age groups. This is because iron deficiency results in impaired intracellular killing in the leucocytes, decreased ability of the lymphocytes to replicate and lowered concentration of cells responsible for Cell Mediated Immunity. In one study in India it was found that anemic children were 5.75 times more susceptible to Lower Respiratory Infections compared with their non-anemic counterparts. The authors concluded that prevention of anemia will reduce the incidence of LRTI.
29
16 15

5.

Suboptimal utilization of energy sources by the muscle cells. Iron deficiency causes impaired work performance in adults and adolescents with even mild iron deficiency without anemia.

6.

Breath-holding Spells: Iron deficiency is implicated in the causation of breath-holding spells in infants and young children. Iron supplementation results in decrease in the frequency of breathholding spells.
17-19

7.

Increased risk of Febrile Seizures: Studies show that children with iron deficiency have a greater chance of having febrile seizures than their non iron-deficient counterparts.
20-22

8.

Heart and Lung Disease: Ischemic Heart Disease and symptoms of Chronic Lung Disease are worsened by iron deficiency.

9.

Cold Intolerance: Chronic iron deficiency causes cold intolerance in one-fifths of the patients by interfering with thyroxin and catecholamine metabolism. This may manifest as neuralgia, tingling and numbness and vasomotor disturbances.

10. Increased heavy metal absorption: Divalent metals like zinc and cadmium are absorbed excessively in the presence of iron deficiency leading to their toxicity. 11. Pseudotumour Cerebri: Iron deficiency is one of the causes of this condition also known as Benign Intracranial Hypertension. 12. Iron deficiency in Pregnancy: Iron deficiency increases the maternal mortality and morbidity, perinatal mortality and prematurity. Infants of iron deficient mothers develop anemia earlier and require more iron than that available in breast-milk.
23, 24

Iron Absorption
The absorption of iron from the gut depends upon various parameters of which the following are of clinical importance having therapeutic implications 1. Forms of Iron Iron is available as a) Heme and b) Non-heme forms. The latter in turn can be either ferrous (divalent) or ferric (trivalent) Heme iron is absorbed from the gut as intact metalloprotein and is not chelated by dietary factors like phytin and tannins. It may thus appear to be the ideal form of iron for supplementation. However, free heme in the gut rapidly polymerizes itself and becomes
30

unavailable for absorption. Therefore, free heme is not the ideal form of iron for pharmacological use. The ferrous and ferric forms of iron have different absorption pathways, namely the Divalent metal transporter 1 (DMT1) pathway for the ferrous form and the Beta 3 Integrin and the Mobilferrin pathways for the ferric form. 2. Inhibitors of Iron Absorption Many factors that are commonly found in the diet are potent inhibitors of iron absorption. Some of the common inhibitors are phytates (present in cereals, legumes, nuts and seeds), calcium (found in milk and milk products) and tannins (present in tea, coffee and cocoa). 3. Enhancers of Iron Absorption. Hemoglobin iron present in the meat and poultry, Vitamin C found in fruits, juices, potatoes and vegetables such as green leaves, cauliflower and cabbage and condiments such as Soya sauce enhance the absorption of iron several fold. Knowledge of these modifiers of iron absorption is useful for the clinician who can make appropriate adjustments in the patients' diet while on medicinal iron.

Diagnosis of Anemia
For practical purposes anemia is classified as mild when the hemoglobin is 10 and above, moderate when it is between 7 and 9.9, severe when it is below 7 and very severe when it is below 4 (all values expressed as grams per dL). 1. Clinical examination Clinical Examination is not very reliable for the diagnosis of anemia. Sensitivity of diagnosing anemia is only 66 percent when the hemoglobin is in the range of 5 to 8 grams and 93 percent when it is below 5 g / dL.25 Examination of palm for pallor is more reliable in children because of the frequency of conjunctivitis in this age group.
26 25-27.

2. Investigations Since the clinical examination is not very reliable, investigations are essential to confirm and quantify the anemia. a. Hematological Tests These are the basic tests required to diagnose anemia and include Hemoglobin estimation, peripheral blood smear, and reticulocyte count. However, as already mentioned, anemia is a rather late manifestation of iron deficiency and therefore other tests are essential to diagnose iron deficiency in the early stages. b. Tests to diagnose Iron deficiency: The important tests that are used to diagnose iron deficiency are Serum Iron, Serum Ferritin, Serum Transferrin (Total Iron Binding Capacity) and Serum Transferrin
31

receptor level. i. Serum Ferritin: This is the best single test for diagnosing iron deficiency . The only disadvantage is that Ferritin is an acute phase reactant and therefore is elevated in chronic inflammatory states. Thus, while a low serum ferritin level is diagnostic of iron deficiency a normal level in the presence of chronic inflammation does not exclude iron deficiency. A level less than 15 g per liter is diagnostic of iron deficiency. ii. Serum Transferrin Receptor levels (sTfR) This is a relatively new test and therefore not widely available. It is as sensitive as Serum Ferritin levels and it has the advantage of not being affected by chronic inflammation.
28-32 2, 2 41

The normal range is 3-9 mg/L. In iron deficiency s TfR is elevated to above 9 mg/L

A practical and inexpensive method of diagnosing iron deficiency is to assess the response to iron therapy. Iron deficiency is confirmed if the Hb rises by 1 g/dL or the Hematocrit rises by 3% following a 4 week course of iron therapy in the dose of 3 mg/kg/day of elemental iron.
33

Another useful test to diagnose IDA in its early stages is the Red Cell Distribution Width (RDW). This is an index of the variation of red cell size and can detect subtle degrees of anisocytosis. Thus, elevated RDW is the earliest sign of IDA and is more sensitive than a peripheral blood smear in the diagnosis of IDA. It is also more sensitive than serum iron, ferritin or Total Iron Binding Capacity (TIBC). The normal range of RDW is 11.5 to 14.5
TABLE 4: Severity of Anemia
Severity Mild Moderate Severe Very Severe Hemoglobin (g /dL) 10 and above 7 to 9.9 Below 7 Below 4
34

Treatment Any underlying cause for the iron deficiency like occult bleeding, worm infestation should be identified and treated. Iron therapy Iron is available as various compounds. The compound of choice is ferrous sulfate because of its 42 proven track record in terms of safety, efficacy and their low cost. The dose is 6 mg of elemental iron per kilogram body weight per day. (WHO, however,
32

recommends 3 mg instead of 6 mg 4). Iron therapy should be continued for a few months after the hemoglobin has increased to acceptable levels in order to build up adequate stores in the body. The percentage of elemental iron in various salts is given in the following table. TABLE 5: Percentage of Elemental Iron in the commonly available preparations
Preparation Anhydrous Ferrous Sulfate Crystalline Ferrous Sulfate (7 H2O) Ferrous Fumarate Ferrous Gluconate Ferrous Succinate Colloidal Iron Percentage of Elemental Iron 37 20 33 12 23 50

Newer Iron Preparations Many newer forms of iron preparation are now available in the market with claims about their superiority. However none of these have been found to be superior to ferrous sulfate in terms of 42 cost effectiveness. The following are some of the newer preparations. a. Iron Hydroxide Polymaltose. This preparation made a huge splash when it was launched and it was claimed to be superior to the older preparations!35 But several studies both in India and abroad have concluded that this compound is inferior to Ferrous Sulfate. A few studies have even found it to be totally 36-38 ineffective. Carbonyl Iron. It is said to be very safe. Side effects are very minimal and the liquid preparation does not stain the teeth (The last mentioned may be a consideration particularly among children of the higher socioeconomic group). It is as effective as ferrous sulfate. The greatest advantage is its safety profile. Doses as high as 1000 to 10,000 mg have been tolerated without side effects in non-anemic and anemic adult volunteers and risk of iron poisoning in children 39,40 can be eliminated by its use. Sodium Iron EDTA. It is very safe and effective. It is not affected by the presence of iron absorption inhibitors like phytates and tannins in the diet. It is particularly 43, 44 useful in food fortification.

b.

c.

d. Iron Ascorbate: Safe and effective. As mentioned early an effort must be made to identify the cause of the iron deficiency such as helminthiasis, chronic malaria, and occult gastrointestinal bleeding like Meckel's Diverticulum and appropriate treatment instituted.
33

Prevention of Iron Deficiency Since the effects of iron deficiency, particularly those on the developing brain, in young children are irreversible it is vital that iron deficiency be prevented at all cost. Prevention of iron deficiency is fairly easy if the doctor is sensitized to the issue. The following are the groups that should be targeted for preventive measures. TABLE 5: Groups to be targeted for Iron supplementation to prevent IDA
Population group Low Birth Weight Infants 2 to 23 months of age Normal Infants 6 to 23 months of age * Children 24 to 59 months of age * School Aged children * (above 60 months age) All women of child bearing age * Pregnant and Lactating Women Dosage Schedule 2 mg / kg / day 2 mg / kg / day Duration of Supplementaion 2 months to 23 months of age 6 months 23 months of age
4

2 mg / kg / day up to 30 mg 3 months Iron: 30 mg / day Folic Acid: 250 :g / day Iron: 60 mg / day Folic Acid: 400 :g / day As above 3 months 3 months Throughout pregnancy

* In communities where prevalence of iron deficiency is 40 percent or more 4 Tips for preventing IDA in infants and toddlers
v v v v v

Encourage breast feeding for at least 1 year Use iron containing weaning food Do not use unmodified cow's milk for infants less under 1 year of age Encourage the use of iron rich vegetables like green leafy vegetables, beans, peas Promote use of meat wherever it is acceptable.

Eating practices that promote iron absorption from gut

v v

Do not drink coffee, tea at meal-time. Tea drinking to be postponed to 2 hours after meals Use milk, cheese and other dairy products as between-meal snack rather than at mealtime.

Key Points
v v v v

Iron deficiency (ID) is a universal problem in children and women of child-bearing age. ID is a systemic disease and not merely a hematological disease. Impairment of cellular functions occurs in iron deficiency even when there is no anemia. ID can cause irreversible cognitive and learning disabilities with an overall reduction in the IQ. All children and women in the reproductive age group require prophylactic low dose medicinal iron to prevent iron deficiency.

34

References
1. 2. 3. 4. 5. 6. 7. 8. 9. Deeksha Kapur et al. Nutritional Anemia and its Control. Indian J Pediatr 2002;69 (7):607616 WHO 1968. Nuritional Anemias: report of a WHO scientific Group, WHO, Geneva, Switzerland). George Buchanan. The tragedy of iron deficiency during infancy and early childhood. J Pediatr 1999;135:413-5 Iron Deficiency Anemia Assessment, Prevention and Control A guide for program managers. UNICEF, UNU, WHO 2001. DeMaeyer EM, Adiels-Tegman M. The prevalence of anemia in the world. World Health Stat Q 1985; 38:302-316. Draper, A. (1997) Child development and iron deficiency. The Oxford Brief, pp.16. INACG (International Nutritional Anemia Consultative Group), Washington,DC Indian Medical Association 2006. http://www.imanational.com/Anaemia.htm# Lozoff et al. Iron deficiency anemia and iron therapy effects on infant developmental test performance. Pediatrics 1987; 79(6):981-95 Lozoff et al. Abnormal behavior and low developmental test scores in iron-deficient anemic infants. J Dev Behav Pediatr 1985; 6(2):69-75

10. Walter T. Infancy: mental and motor development. Am J Clin Nutr. 1989;50(3 Suppl:655-61 11. Lozoff et al. Long-term developmental outcome of infants with iron deficiency. N Eng J Med. 1991;325(10):687-94 12. Halterman et al. Iron Deficiency and Cognitive Achievement among school-aged children and adolescents. Pediatrics 2001;107:1381-1386 13. Sen and Kanani. Deleterious functional impact of anemia on young adolescent school girls. Indian Pediatr 2006; 43(3):219-226 14. Mani et al. Cardiovascular Response in Anemia. Indian J of Pediatr 2005; 72:297-300 15. Mullick et al. Impact of iron deficiency anaemia on T lymphocytes & their subsets in children. Indian J Med Res. 2006 Dec;124(6):647-54 16. Ramakrishnan and Harish. Hemoglobin level as a risk factor for LRTI. Indian J Pediatr 2006; 73 (10) : 881-883 17. Colina KF, Abelson HT. Resolution breathholding spells with treatment of concomitant anemia. J Pediatr 1995; 126: 395-397. 18. Daoud AS et al. Effectiveness of iron therapy on breath-holding spells. J Pediatr 1997; 130: 547-550. 19. Bhatia MS, Singhal PK, Dhar NK, Nigam VR, Malik SC, Mu1lick ON. Breath-holding spells; An analysis of 50 cases. Indian Pediatr 1990; 27: 1073-1079.
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20. Daoud et al. Iron status: A possible risk factor for the first febrile seizure. Epilepsia 2002; 43(7):740-743 21. Naveed ur Rehman et al. Association between iron deficiency anemia and febrile seizures. L Coll Physicians Surg Pak 2005 Jun; 15(6):338-40 22. Pisacane et al. Iron deficiency anemia and febrile convulsions. BMJ 1996; 313:343 23. Goyer RA. Nutrition and metal toxicity. Am J Clin Nutr 1995 Mar;61(3 Suppl):646S-650S 24. Peraza MA et al. Effects of micronutrients on metal toxicity. Environ Health Perspect 1998 Feb;106 Suppl 1:203-216 25. Luby SP et al. Using clinical signs to diagnose anemia in African children. Bull World Health Organ. 1995; 73(4):477-82 26. Zucker et al. Clinical signs for the recognition. Bull World Health Organ. 1997; 75 Supple 1:97-102 27. Sdepanian VL. Diagnostic limitationsRev Assoc Med Bras 1996; 42(3):169-74 28. Skikne et al. Serum transferring receptor: A quantitative measure of tissue iron deficiency. Blood1990;75:1870-76 29. Cook JD. The measurement of serum transferring receptor. Am J Med Sci 1999 Oct;318(4):296-76 30. Lin XM et al. Levels of Serum transferring receptor. Br J Nutr 2006 Dec;96(6):1134-9 31. Drew & O'Shaughnessy. Recent Advances in hematology. BMJ 1999;318:991-994 32. Kogo Y et al. Circulating transferring receptor in human serum. Br J Hematology 1986;64:277- 81 33. Recommendations to prevent and control iron deficiency in the US. MMWR 1998 Apr 03; 47 (RR-3). 34. Vishwanath D et al. RDW in the diagnosis of IDA. Indian J Pediatr 2001 Dec; 68(12):1117-9 35. Langstaff RJ et al. Treatment of iron deficiency anemia: a lower incidence of adverse effects with iron polymaltose complex than ferrous sulfate. Brit J Clin Res 1993; 4:191-198. 36. Mehta BC. Ineffectiveness of iron polymaltose in treatment of iron deficiency anemia. J Assoc Physicians India 2003; 51: 419-421 37. Liu TC et al. Comparison of a combination ferrous fumarate product and a polysaccharide iron complex as oral treatments of iron deficiency anemia: a Taiwanese study. Int J Hematol 2004 Dec;80(5):416-20 38. BC Mehta. Iron Hydroxide Polymaltose : Iatrogenic Cause of Persistent Iron Deficiency Anaemia Despite Continuous Oral Iron Therapy; J Assoc Physicians India. 2002 Feb;50:279-80 39. Gordeuk et al. Carbonyl iron therapy for iron deficiency anemia. Blood. 1986 Mar;67(3):745-52)

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40. VR Gordeuk et al. High-dose carbonyl iron for iron deficiency anemia: a randomized doubleblind trial. American Journal of Clinical Nutrition; 46:1029-1034 41. Assessing the Iron Status of Populations. Report of Joint World Health Organization / Centers for Disease Control and Prevention Technical Consultation on the assessment of Iron Status at the population level. Geneva, Switzerland 2004. pp 16. 42. Technical Consultation on Strategies for prevention and control of iron deficiency anemia amongst under three children in India. Indian Pediatrics 2002; 640-47. 43. Bothwell TH. Iron fortification with special reference to the role of iron EDTA. Arch Latinoam Nutr 1999; 49(3 Suppl2):23S-33S 44. Huo J et al. Therapeutic effect of NaFeEDTA-fortified soy sauce in anemic children in China. Asia Pac J Clin Nutr 2002; 11(2):123-7

37

Anemia in Adolescents

Dr. Sheela V. Mane Consultant Anugraha Hospital Bhagwan Mahaveer Jain Hospital Bangalore

Adolescence is a significant period for physical growth and sexual maturation. Nutrition being an important determinant of physical growth of adolescents, is an important area that needs attention. More than two thirds of the adolescent girls suffer from anemia. Anemic adolescent mothers are at a higher risk of miscarriages, maternal mortality and giving birth to stillborn and underweight babies. Anemia in children and adolescents is often not a well appreciated and recognized problem, but is an important impediment to physical and cognitive development. The most common anemia in adolescents is that due to iron deficiency. 30-90% of adolescent children in India are anemic depending upon socio-economic condition and whether they are from rural or urban area. Basal requirement of iron during this period is 3mg/kg/day in female taking into account both basal, and menstrual loss together. The cumulative effect of continuing high iron needs and tendency of young women to eat less than men, probably explains why the prevalence of I.D.A among females appears to increase through out adolescence. In females the increase in the iron need is distributed over a longer period than in male. Girls have their growth peak earlier than boys at mean age of 11.5 years of age with 95% from 9.7 to 13.3years. Tanner stage 2 to 5 begins a year before peak growth and continues for a total of about 4 years, with menstruation typically starting about 1 year after peak growth. There is a higher requirement of iron for the female as compared to male during adolescent period and reproductive age period due to blood loss during menstruation, pregnancy and lactation. Iron loss during menstruation is estimated to be 16mg/kg/day.The overall iron requirement increases from a pre-adolescent level of 0.7-0.9 mg/day, to as much as 2.2 mg/day or perhaps more in heavily menstruating young women. The mean requirement for absorbed iron reaches to about 1.5mg/day at peak growth. Hence adolescents girls are unlikely to acquire substantial iron stores during this period because intake may average as little as 10-11 mg iron/day. The low iron store during this period in these young women of reproductive age will make them susceptible to I.D.A during pregnancy because dietary intake alone is insufficient in most cases to meet the requirement of pregnancy. The importance of nutritious diet during this period in a woman's life cannot be overemphasized. There are certain factors which contribute to dietary imbalances in this period.

38

Factors influencing nutrition of adolescents

Common factors
1. Conditioning factors v Infectious diseases are important factors responsible for malnutrition, particularly in children and adolescents. Diarrhoea, intestinal parasites malaria and tuberculosis all contribute to malnutrition. v Poor environmental sanitation also leads to repeated bouts of infections. v Girls lose a considerable amount of iron (average 1 mg daily) during Therefore, they require additional iron rich foods and supplements. 2. Cultural factors v Food habits, customs, beliefs, traditions and attitudes. v Religion v Food fads v Cooking practices v Social customs 3. Socio-economic factors Malnutrition and anemia are largely a by-product of poverty, ignorance, insufficient education, lack of knowledge regarding nutritive value of foods, large family size, etc. 4. Gender issues Girls and young women are discriminated against in both quantity and quality of food. On top of this, they are married early and suffer early pregnancy and child birth further compromising their nutritional status. menstruation.

Factors specific to adolescents

Adolescents have a world of their own and have different eating patterns that influence their nutrition. Adolescence is a period of emergence of an individual into a more independent phase of life, which influences food behavior also. There is a lack of a sense of urgency regarding future health. Family meals become less important. They tend to break away from family eating patterns and succumb to unbalanced diets under influence of peers, mass media. Personal self esteem and body image guide the eating behavior. Missing meals especially breakfast is extremely common. SHAHN Survey-2002 among Delhi school students, reveals that 30% boys and 40% girls skip one meal everyday and breakfast is the commonest casualty (54%). So how can one address this problem in the adolescents?

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Role at community level Healthcare providers must educate the community to provide education on importance of adolescent nutrition and influence the adverse socio-cultural practices. Education regarding balanced diet for both boys and girls: v provide education on the importance of nutrition for adolescents themselves and on their offsprings v promote good food selection and safe cooking practices v promote concept of kitchen garden where green leafy vegetables etc. can be grown at a very low cost v create awareness in community to factors contributing to malnutrition and nutritional anaemia, especially in girls. v Involve other functionaries like AWW, schoolteachers, ASHAs to identify and tackle nutritional problem. v create awareness in community about role of malaria and hookworm infestation in causing and aggravating anaemia Role of individual counseling Following tips can be used for counseling parents v Food should be attractively served, with variety in colour, shape, size and texture. v Likes and dislikes of the adolescent should be kept in mind v Impress upon them that the growing bodies of the adolescents need balanced and wholesome diet, missing meals is deleterious for health and breakfast is very important for a good beginning of the day v Snacks should be wholesome and nutritious v Most of whole pulses should be included in diet v Occasional consumption of `junk food`may be allowed v Highly fatty foods should be avoided v Adolescent should be encouraged to exercise their choice and responsibility of foods v The diets of girls need special emphasis on iron rich food, like leafy vegetables whole gram cereals, dry fruit, egg, jaggery etc. The iron requirement is high because of menstrual losses and growing phase. Food fads, and anemia in adolescent children Adolescents are more likely to skip meals at home,eat irregularly,make excessive use of less nutritious snack food (junk foods). Young women often eat less than dictated by their appetite, out of fear of obesity.
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Basic approach to prevention of IDA includes: Education to increase dietary iron intake. Fortification of staple food with iron and introduction of iron containing food in the diet Control of infection, worm infestation. Pharmacological iron supplementation. Food fortification is one of the most effective ways of prevention of iron deficiency. Fortification of suitable food vehicles with absorbable forms of iron is a highly desirable approach in controlling iron deficiency. Iron supplementation is essential for the rapid treatment of severe iron deficiency anemia as well as for prophylaxis and prevention of anemia in both sex and age groups. Supplementation with oral iron tablet or syrup is the most widely used approach to control global problem of iron deficiency anemia. Under adolescent girls' scheme, it is proposed to provide 100mg of elemental iron daily to all adolescent girls every year for 100 days. Addition of 25mg of vit C to iron folate tablet has shown a higher Hb response as compared to iron folate tablet alone in adolescent girls. The most common form of iron in iron tablet is ferrous sulfate (20%iron) although fumarate (33%iron) and gluconate (20%iron) are some times used. Based on a recent multicentric study in India it is now recommended that adolescent girls on attaining menarche should be given weekly dosage of the IFA tablet containing 100mg elemental iron and 500ug folic acid once a week accompanied by appropriate dietary supplementation. Key Points
vUndernutrition in adolescence has long-term effects on their productivity vMalnutrition in adolescence has serious implications with regard to predilection for

degenerative diseases in adult life as well as for the health of next generation
vChronic energy deficiency and stunting is common but severe malnutrition is rare vSubclinical micronutrient deficiencies are common because of increased requirements.

Iron deficiency is the most common deficiency. Other common nutrient deficiencies include that of vit A, folic acid, iodine, zinc and calcium. Deficiency of iodine and folic acid in pregnant adolescent can cause irreparable damage to fetus.
vMalnutrition and micronutrient deficiencies are more common in poor socio-economic

strata and among pregnant adolescents.

vPrinciples of management of severe malnutrition are similar to young children.

References : ARSH WHO Module Bhave's 'TEXT BOOK OF ADOLESCENT MEDICINE'

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Bolt from the Blue Anemia due to Obstetric Hemorrhage

Dr. Prakash K. Mehta Chief, Division of Maternal Fetal Medicine Bhagwan Mahaveer Jain Hospital Asha Pregnancy Care centre, Bangalore. Introduction: Obstetric Hemorrhage is the most common cause of acute anemia as well as maternal death .It is estimated that one woman dies every 4 minutes due to this catastrophe. In addition to death, serious morbidity may follow hemorrhage. Sequelae include adult respiratory distress syndrome, coagulopathy, shock, loss of fertility, and pituitary necrosis (Sheehan syndrome). Causes: Massive obstetric hemorrhage may be antepartum or postpartum Antepartum Hemorrhage Early Pregnancy: Causes of hemorrhage in early pregnancy may be abortion, ectopic or molar pregnancy. Late pregnancy: If bleeding occurs in later pregnancy or during labor but before delivery, placenta previa, abruptio placentae or ruptured uterus have to be suspected Placenta Previa : It occurs in one in every 200 pregnant women, most often in the third trimester. The classic presentation of placenta previa is painless vaginal bleeding and a soft, non tender uterus. All patients with placenta previa should be informed of the risk of severe PPH, including the possible need for transfusion and hysterectomy. Blood may distend the uterus and prevent effective contraction Bleeding begets bleeding Placenta accreta. This is a rare disorder, occurring in only 1 in 5000 pregnancies. 9 to 10% of cases of placenta previa are associated with placenta accreta, an abnormally firm attachment of the placenta to the wall of the uterus. This condition most commonly occurs in women who have had previous uterine surgery. Placenta accreta prevents the placenta from separating from the uterine wall at the time of delivery and can cause severe bleeding that often necessitates hysterectomy. Placental abruption. Since ultrasound examination has a high false-negative rate in diagnosing abruption, this obstetric complication is diagnosed clinically The management of abruptio placentae is primarily supportive and entails both aggressive hydration and monitoring of maternal and fetal well-being. Coagulation studies should be performed, and fibrinogen and D dimer or fibrin degradation products should be measured to screen for disseminated intravascular coagulation. Packed red blood cells should be typed and held. If the fetus appears viable but compromised, urgent cesarean delivery should be considered.
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Uterine rupture. In women who have had a previous Caesarean birth, a disruption of the surgical scar in the uterus is a rare but dangerous cause of vaginal bleeding, intense abdominal pain and abdominal tenderness. The presentation of uterine rupture may be similar to that of abruptio placentae. Treatment includes aggressive resuscitation and urgent surgical delivery. Others: .Cervical varix during pregnancy is a rare condition. The conventional approach to cervical varices during pregnancy is expectant management and bed rest. The placement of a cerclage may result in absence of vaginal bleeding during pregnancy. Ectopic deciduosis is usually no more than a pathologic curiosity. In a pregnant patient with spontaneous intraperitoneal hemorrhage, however, it must be considered because it results in a high incidence of maternal and neonatal mortality. Postpartum Hemorrhage The average blood loss at the time of delivery is approximately 500 ml during a vaginal delivery and 1,000 ml during a cesarean section. Excessive blood loss or "postpartum hemorrhage" complicates approximately 4% of vaginal deliveries and 6-7% of cesarean sections. Estimates of blood loss at delivery are subjective and generally inaccurate. Studies have suggested that caregivers consistently underestimate actual blood loss. Another consideration is the differing capacities of individual patients to cope with blood loss. A healthy woman has a 30-50% increase in blood volume in a normal singleton pregnancy and is much more tolerant of blood loss than a woman who has preexisting anemia, an underlying cardiac condition, or a volume-contracted condition secondary to dehydration or preeclampsia. Lack of experienced obstetricians, blood transfusion services, anesthetic services, and operating capabilities also play a role for the less favorable outcome of PPH. Risk Factors include PPH in a previous pregnancy, retained placenta, failure to progress during the second stage of labor, placenta accreta, lacerations, instrumental delivery, large for gestational age, over distension of the uterus, hypertensive disorders and induction of labor and augmentation of labor with oxytocin Causes: The causes for PPH can be remembered by mnemonic 4 Ts: tone, tissue, trauma, and thrombosis (Society of Obstetricians and Gynecologists of Canada, 2002). Tone: Uterine atony is the commonest cause for PPH and account for 90% of cases. Uterine atony and failure of contraction and retraction of myometrial muscle fibers can lead to rapid and severe hemorrhage and hypovolemic shock. Tissue: The placenta is more likely to be retained at extreme preterm gestations (especially <24 wk), and significant bleeding can occur. Retention of a portion of the placenta is more common if the placenta has developed with a succenturiate or accessory lobe. Failure of complete separation of the placenta occurs in placenta accreta and its variants.

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Trauma: Damage to the genital tract may occur spontaneously or through manipulations used to deliver the baby. Continuing hemorrhage in a patient with a firm uterine fundus may indicate a hidden vaginal or cervical laceration. This type of injury is easier to identify and repair with adequate lighting, exposure and assistance. Uterine rupture can occur with previous cesarean delivery scars. Any uterus that has undergone a procedure resulting in a total or thick partial disruption of the uterine wall should be considered at risk for rupture in a future pregnancy. This includes myomectomy; uteroplasty for congenital abnormality; cornual or cervical ectopic resection; and perforation of the uterus during dilatation, curettage, biopsy, hysteroscopy, laparoscopy, or intrauterine contraceptive device placement. Trauma may occur following very prolonged or vigorous labor, especially if the patient has relative or absolute cephalopelvic disproportion and the uterus has been stimulated with oxytocin or prostaglandins Trauma also may occur following extra uterine or intrauterine manipulation of the fetus. The highest risk is probably associated with internal version and extraction of a second twin; however, uterine rupture may also occur secondary to external version. Finally, trauma may result secondary to attempts to remove a retained placenta manually or with instrumentation. While puerperal hematomas typically cause a vulvar or vaginal mass, an occult retroperitoneal hematoma can present with severe abdominal pain and shock after delivery. Visible hematomas that are less than 4 cm in size and not expanding may be managed with ice packs and observation. Larger or expanding hematomas must be incised, irrigated and packed, with ligation of any obvious bleeding vessels Thrombosis: If uterine exploration is non diagnostic and the fundus is firm, rarer causes of hemorrhage should be considered. If venipuncture sites are oozing, coagulopathy should be considered. Thrombocytopenia may be related to preexisting disease, such as idiopathic thrombocytopenic purpura, or acquired secondary to HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), abruptio placentae, disseminated intravascular coagulation (DIC), or sepsis. Rarely, functional abnormalities of platelets may also occur. Most of these are preexisting, although sometimes previously undiagnosed. . Finally, dilutional coagulopathy may occur following massive PPH and resuscitation with crystalloid and packed red blood cells (PRBCs). Management: General: v Accurate estimation of blood loss v Prompt recognition and treatment of clotting disorders v Multidisciplinary approach v Use of adequately sized intravenous cannula v Importance of monitoring central venous pressure. v Arrangement of adequate quantity of blood
44

Protocol : v Assessment - Gathering information v Diagnosis - Interpreting the information v Planning - Developing the care plan v Intervention - Implementing the care plan v Evaluation - Evaluating the care plan As with any emergency, the assessment of obstetric hemorrhage begins with the ABCs (airway, breathing and circulation). A delay in the correction of hypovolemia, diagnosis and treatment of defective coagulation and/or surgical control of bleeding are the avoidable factors in most maternal deaths caused by hemorrhage. The main goal is to maintain effective circulating intravascular volume by prompt and adequate replacement of blood, crystalloids or fresh-frozen plasma through more than one intravenous line (it might be necessary to pump blood under pressure) with constant monitoring of the pulse rate and the arterial blood pressure. The rapid correction of hypovolemia with crystalloids and red cells is the first priority, followed by blood component therapy.
Continuous slow bleeding or sudden bleeding is an emergency Intervene early & aggressively

Lab Studies: Once the diagnosis of PPH has been made, a CBC and baseline coagulation studies should be performed. Initially, the hemoglobin value does not reflect the amount of blood loss. Initial coagulation study findings are usually within reference ranges; however, abnormalities may be noted. This is most common when PPH is preceded by abruptio placenta, HELLP syndrome, and fatty liver of pregnancy, intrauterine fetal demise, embolic events, or septicemia. If the International Normalized Ratio and/or activated partial thromboplastin time are elevated, the use of fibrinogen, a thrombin time measurement, D-dimers, and a blood film should be considered. In late pregnancy, fibrinogen levels are 2-3 times the upper reference range limit in the nonpregnant state, and a level within the nonpregnant reference range should be viewed with caution if the clinical picture suggests coagulopathy. Imaging Studies: The onset of PPH is generally rapid. With proper diagnosis and treatment, resolution usually occurs before further laboratory work or imaging can be undertaken. In experienced hands, bedside ultrasound may help reveal clots or retained products; however, the treatment of PPH includes manual exploration if bleeding persists. This renders ultrasound redundant in the acute setting at a time when treatment must not be delayed. Antenatal ultrasound is indispensable for detecting high-risk patients with predisposing factors for PPH,
45

such as placenta previa, and is becoming increasingly sensitive and specific in the diagnosis of placenta accreta and its variants Treatment : When uterine atony is the cause of postpartum hemorrhage, treatment is fundal massage and uterotonics which could be 10 U of oxytocin in 500 mL of intravenous fluid by continuous drip, 200-250 mcg of ergonovine intramuscularly, or 250 mcg of 15-methyl prostaglandin F2-alpha intramuscularly.. Modern management of atonic PPH entails the use of prostaglandins administered parenterally, orally, rectally, or vaginally. Each has advantages and disadvantages in terms of efficiency, availability, cost, stability, and ease of administration. The use of misoprostol and a long-acting oxytocin analogue (carbetocin) is being studied for this use If the placenta has been delivered, inspection findings suggest whether portions of it have been retained. If it is undelivered or if retained clots or placental fragments are distending the uterus and bleeding is persisting despite appropriate ongoing treatment, manual exploration and removal should be undertaken. This is simultaneously therapeutic by emptying the uterus and permitting contraction while also aiding in the diagnosis of placenta accreta and uterine rupture. Cervical and vaginal lacerations may also be palpated at this time. In addition to the appropriate use of oxytocic agents for uterine atony, surgical techniques, including uterine tamponade, major vessel ligation, compression sutures, and hysterectomy, may be required. All gynecologists should be able to perform without delay the operative maneuvers which are necessary to control the bleeding, including hypogastric artery ligation, or even emergency hysterectomy. Bimanual compression, uterine packing, and such surgical interventions as B-Lynch suture, ligation of uterine artery, ovarian artery, and internal iliac artery, and embolization are effective methods for controlling intractable hemorrhage. Uterine Tamponade: Attempting to compress the uterine sinuses and to stop bleeding via uterine packing is a reasonable option for management of PPH. A good packing technique entails careful layering of the ribbon gauze pack to occlude the whole space of the uterine cavity, which is much easier in theory than in practice. Sengstaken-Blakemore tube and a Rusch urologic hydrostatic balloon catheter have been used for this purpose. An inexpensive and easily available alternative is to use an inflated condom as a tamponade. With aseptic precautions, a sterile rubber catheter fitted with a condom is introduced into the uterus. The condom is inflated with 250-500 mL normal saline according to need. The condom catheter was kept for 24-48 hours, depending upon the initial intensity of blood loss, and gradually deflated when bleeding ceased Ligation techniques: Ligation of the uterine arteries, ovarian arteries and hypogastric arteries will usually control uterine bleeding and arterial embolization is also effective. Uterine artery ligation. When medical management fails, this is a highly effective option. Uterine artery ligation can be effective in 93% of cases, with a 2.2% complication rate. It's a fast procedure, too, taking
46

perhaps 5 minutes for both sides. No. 1 chromic resorbable suture can be used to tie at the level of the internal os and includes 2-3 cm of myometrium. Ligation of the hypogastric arteries: Specific information regarding its effectiveness is lacking. In a study this procedure was effective in controlling bleeding in eight of 19 patients (42%). In these patients, blood loss, operating time, and intraoperative morbidity was increased when compared with a group of patients undergoing emergency hysterectomy for obstetric hemorrhage without prior ligation of the hypogastric arteries, There was also a 10 fold higher urologic injury rate. Ligation of the uterine arteries or hypogastric arteries may be performed; both operations require laparotomies. Bilateral hypogastric artery ligation has a success rate ranging from 40 to 100%.In contrast; uterine artery ligation has been shown to have a success rate of 92% and a complication rate of 1%. Both these techniques aim to leave the uterus intact and preserve fertility. Postpartum hemorrhage that cannot be controlled by local measures has traditionally been managed by bilateral uterine artery or hypogastric artery ligation. These techniques have a high failure rate, often resulting in hysterectomy. In contrast, endovascular embolization techniques have a success rate of >90%.Placement and utilization of arterial catheters for uterine artery embolization is becoming more widespread and new surgical technology such as the argon beam coagulator seems promising. Hysterectomy should also be considered in severe cases. A reluctance to proceed with hysterectomy for obstetric hemorrhage may be a more likely cause of preventable death in obstetrics than a lack of surgical or medical skills. Others: The non-pneumatic anti-shock garment (NASG) exerts lower body counter pressure as a means of returning blood to the central circulation and it tamponades the abdomen and pelvis to decrease further bleeding Recombinant factor VIIa (40-90 mcg/kg, a clotting factor used for hemorrhage in patients with factor deficiencies undergoing testing for hemorrhage from several other sources including variceal and obstetric) has been reportedly dramatically effective in several case reports and a case series for PPH refractory to oxytocin. Data Analysis : The Division of Maternal Fetal Medicine at Bhagwan Mahaveer Jain Hospital is a referral centre for high risk pregnancies. During the years 2005 -06, there were 41 patients with massive obstetric hemorrhage requiring intensive care. 9 patients were referred with APH of which 2 patients with massive DIC and ARF died. 3 of these patients had PPH also. There were 35 patients with postpartum hemorrhage requiring intensive care, of which 4 died. Atonic PPH was present in 7 patients, while the rest were with background of DIC, HELLP or adherent placenta. DIC associated with massive hemorrhage was identified in 18 patients .HELLP syndrome worsening the bleeding was present in 21 patients. Four of the patients had infective hepatitis leading to PPH while AFNL was identified in 3 patients. Majority of the patients had multiple associated factors leading to hemorrhage with HELLP and PIH being the commonest. HELLP
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was unidentified in 10 of the patients. Identification of this disorder and investigations including hematocrit, platelet count and liver enzymes could have possible led to early intervention and prevented these catastrophes. Obstetric hysterectomy was required for 6 patients. 3 hysterectomies were done for placenta previa accreta , 2 were for atonic PPH with DIC and one for rupture uterus. Arterial embolization was considered for 3 patients but either because of associated factors like massive DIC or constraint of time, alternative management methods were used. Uterine tamponade with roller gauze packing was done in 11 patients .Packing was done post C. section in 7 patients. 2 patients had to be packed following vaginal delivery. 2 patients who continued to bleed even after Ob hysterectomy settled down with packing.. Massive transfusion was required for 30 patients. Majority of these patients were referred in shock or after the onset of DIC. Awareness, suspicion and early referral can reduce the morbidity and avert mortality. Conclusion: Life-threatening hemorrhage requiring immediate treatment affects only 1 in 1000 deliveries. It will therefore occur about four times a year in a large maternity hospital. This is infrequent enough to make practice drills necessary. With so many treatment options, ultimately the choice of technique becomes one of individual preference, institutional availability and the individual clinical scenario. Timely hysterectomy should be performed for signs of refractory bleeding. Application of medical and surgical principles combined with recent technologic advances will help the obstetrician avoid disastrous outcomes for both mother and fetus.

Accidental hemorrhage

Uterine rupture

Blood loss and effects

Blood Volume Loss 500 -1000 (10 - 15%) 1000 -1500 mL (15 - 25%) 1500 -2000 (25-35%) 2000-3000 mL (35-50%) Blood Pressure (systolic) Normal Slight fall (80-100 mm Hg) Moderate fall (70-80 mm Hg) Marked fall (50-70 mm Hg) Symptoms and Signs Palpitations, tachycardia, dizziness Weakness, tachycardia, sweating Restlessness, pallor, oliguria Collapse, air hunger, anuria
48

Degree of Shock Compensated

Mild

Moderate Severe

Adapted from Int J Gynaecol Obstet 1997 May; 57(2): 219-26

Antepartum Vaginal Bleeding

Massive Bleeding

Call for help Evaluate ABCs (airway, breathing, circulation) Administer intravenous fluids Administer supplemental oxygen Consider transfusion Consider urgent cesarean delivery

History and physical examination Fetal monitoring

Normal bloody show

Severely distressed fetus (especially if the bleeding began abruptly with the rupture of membranes)

Uterine pain?

Inflamed cervix or mucopurulent discharge

Routine evaluation

No pain or pain only with contractions; nontender fundus

Pain between contractions or tender fundus

Probable cervical infection

Culture and treat as appropriate

Suspect vasa previa

Suspect placenta previa

Consider abruptio placenta

Consider uterine rupture (especially if fundus is expanding)

Immediate ultrasound examination if available

Monitor fetus and mother supportive care

Distressed fetus

Death of fetus

Urgent cesarean delivery

Cesarean delivery if in labor

Consider urgent cesarean delivery

Vaginal delivery

Consider urgent laparotomy

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Postpartum hemorrhage

Abdominal pain and shock withour vaginal bleeding(rare)

Oozing from venipuncture sites(rare)

Massive bleeding

Consultation for possible retroperitoneal hematoma

Consider coagulopathy Coagulation studies

Call for help Evaluate ABCs (airway, breathing, circulation) Administer intravenous fluids Administer supplemental oxygen Consider transfusion

Placenta delivered?

No

Yes

Manual exploration of uterus

Vigorous fundal massage Oxytocin, 10 to 30 units administered rapidly in 1L of intravenous saline

Indistinct cleavage plane

Distinct cleavage plane

Firm fundus, still bleeding

Soft fundus, still bleeding

Consider placenta accreta

Manual extraction of placenta

Explore for cervical, vaginal or vulvar lesions

Consultation for probable urgent hysterectomy

Vaginal or vulvar hematoma

Vaginal or cervical laceration

No lesions

Presumed uterine atony

Bimanual compression of uterus while awaiting help

Repair Up to 4 cm and stable 4 cm or larger and expanding

Manual exploration of uterus

Continued fundal massage Methylergonovine(Methergine), 0.2 mg given intramuscularly (if the the patient does not have hypertension) or Carboprost(Hemabate) 250 :g intramuscularly

Ice packs, observe

Incise, drain and pack

Retained placenta or clots

Uterine rurpture

Uterine inversion

Nothing found

Remove

Resuscitation Urgent laparotomy

Resuscitation Replace uterus

Seek consultation Repeat algorithm

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Bibliography: 1. Alvarez M, Lockwood CJ, Ghidini A: Prophylactic and emergent arterial catheterization for selective embolization in obstetric hemorrhage. Am J Perinatol 1992 Sep-Nov; 9(5-6): 441-4 2. Bobrowski RA, Jones TB: A thrombogenic uterine pack for postpartum hemorrhage. Obstet Gynecol 1995 May; 85(5 Pt 2): 836-7. 3. Haynes J: Use of recombinant activated factor VII in massive obstetric hemorrhage Int J Obstet Anesth. 2007 Jan; 16(1):40-49. 4. Dildy GA: Postpartum hemorrhage: new management options. Clin Obstet Gynecol 2002 Jun; 45(2): 330-44 5. Wittich AC, Salminen ER, Hardin EL: Uterine packing in the combined management of obstetrical hemorrhage. Mil Med 1996 Mar; 161(3): 180-2 6. Hayman RG, Arulkumaran S, Steer PJ. Uterine compression sutures: surgical management of postpartum hemorrhage. Obstetric Gynecol 2002; 99: 5026 7. Mason BA. Postpartum haemorrhage and arterial embolization. Curr Opin Obstet Gynecol 1998; 11: 4759 8. Rizvi F, Mackey R, Barrett T, McKenna P, Geary M, Successful reduction of massive postpartum hemorrhage by use of guidelines and staff education, BJOJ2004 May;111(5):495-8.

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OFF COLOUR AFTER FORTY

DR. DEVIKA GUNASHEELA, MRCOG (Lond.), Fellow of Reproductive Medicine (RGUHS)

Anaemia is one of the most widespread and often neglected disorders. It is the bane of most underdeveloped countries of the world, and a curse of Indian womanhood. WHO estimates are that two billion people in the world are anaemic, accounting for 30 % of the world's population. Anaemia affects 13 % of the population in the developed world and 44 % in the developing world. Amongst the Asian countries, perhaps Bangladesh and China have a higher incidence of anaemia than India, but Pakistan, Nepal and Sri Lanka have a lower incidence than India. Whereas the incidence of anaemia ranges between 20 and 30 % in the middle income groups, it is much higher in the lower income groups 60 % (urban women) and 70 % (rural women). In geographical areas where malaria and helminthic diseases are endemic, the incidence of anaemia rises to almost 90 %. Anaemia is three times more prevalent in southern Asian women than in European women. It was found that anaemia was less prevalent after the menopause in European women but remained common after the menopause among Indian and Bangladeshi women. The menopausal transition is continuous and not a snapshot in time. In the absence of disease, this process involves changes and irregularity of both bleeding and hormone levels. Irregular bleeding that arises during this period is often subject to medical and surgical investigations and treatment even though the parameters of what are abnormal are not well established. Perimenopause or the recently preferred term The Menopausal Transition (MT) is defined by the WHO as the period in time beginning 2 8 years prior to the Final Menstrual Period (FMP) and lasting upto 12 months after the FMP.
1

Abnormal uterine bleeding is one of the most common complaints during the perimenopausal transition as cycles become more irregular. It has been estimated that menstrual irregularity occurs in more than half of all women. Bleeding can be irregular, heavy or prolonged. The differential diagnosis during these years is vast, as anatomic hormonal, and metaplastic processes have a higher incidence : anovulatory bleeding, uterine leiomyoma, endometrial polyps, adenomyosis, endometrial hyperplasia or endometrial carcinoma. Anovulation and uterine fibroids are the most common hormonal and anatomic causes of abnormal uterine bleeding in the late reproductive age.
52
3 2

The subjective self assessment of uterine bleeding is not at all reliable. 40 % of women with more than 80 ml of objectively quantified menstrual blood loss (an amount that is significantly associated with development of anaemia) described their bleeding patterns as only moderately heavy, whereas 14 % with only 20 ml or less of bleeding found this to be heavy. Only 60 % of women complaining of menorrhagia actually experienced more than 80 ml of menstrual blood loss.
4

HORMONAL THEORIES : Many theories have been put forward to explain the hormonal mechanisms responsible for the vagaries of perimenopausal bleeding. Ample oestrogen levels and prolonged endometrial stimulation in longer anovulatory cycles may well contribute to the rising incidence of endometrial hyperplasia and dysfunctional uterine bleeding as women transverse the MT.
5

ANATOMICAL CAUSES : Leiomyomata and polyps are common in women over the age of 35 and are accepted cause of abnormal uterine bleeding. Uterine fibroids have a prevalence rate of about 25% over the general population. Though rarely malignant, leiomyomata have always been a major contributor to abnormal bleeding or pain and remain the most common diagnosis associated with hysterectomy. Submucous fibroids seem to have a greater effect on bleeding patterns than intramural fibroids but both lead to heavy and prolonged bleeding. DIAGNOSTIC WORKUP : All complaints of irregularity in bleeding patterns may not warrant investigations. But prolonged bleeding (lasting more than 10 days) or intermenstrual (non-cyclical) bleeding are not considered normal and deserve workup. Although polyps and fibroids are the most common anatomical concern one should not overlook the possibility of endometrial carcinoma in the aging female. The incidence of endometrial carcinoma increases with age from 30 39 year old women with the rate of 2.3 / 100,000 women and in the perimenopausal age group (40 49 year old) a further increase to 6.2 / 100,000 women.
1 6

The importance of endometrial biopsy cannot be over emphasized for women with abnormal uterine bleeding during the menopausal transition and also after menopause. The diagnostic approach to a woman with abnormal perimenopausal bleeding has evolved over the last century from operating room curettage to outpatient vacuum suction curettage to eventually the Pipelle plastic catheter. Proponents of the Pipelle catheter cite that it is relatively comfortable for patients. It is reported to have a sensitivity as high as 97.5 % in detecting endometrial carcinoma, but these biopsies were done on woman with known pathology. Of the patients who have had false negative finding by Pipelle sampling, the disease was either confined to a polyp or comprised less than 5 % of cavity
53
7

surface area and therefore was missed. The noninvasive relatively inexpensive and highly reproducible nature of transvaginal ultrasound makes it an especially attractive assessment tool to exclude uterine abnormalities. Significant progress has been made in the evaluation of perimenopausal women using saline infusion hysterosonography (HSN) to help assess the endometrial cavity for focal lesions.
8

HYSTEROSCOPY : Another evaluation that may be helpful in selected cases is hysteroscopy. This allows the identification of endometrial polyps or submucosal fibroids. Goldstein1 has presented an algorithm that utilizes trans vaginal ultrasonography and provides a stepwise approach to working up the perimenopausal patient with abnormal uterine bleeding. If the baseline ultrasound shows a thin distinct endometrial stripe less than or equal to 5 mm in width, a diagnosis of dysfunctional uterine bleeding can be safely made. If the endometrial stripe is thickened to greater than 5 mm or it is difficult to ascertain the endometrial echo, an HSN is warranted for a uterine evaluation. Based on the HSN results, a diagnosis of dysfunctional uterine bleeding can be made, an office endometrial biopsy may need to be taken, or a hysteroscopy with resectoscopic biopsy is performed for final diagnosis and / or therapy. MEDICAL MANAGEMENT : Medical treatment of perimenopausal abnormal uterine bleeding is either hormonal or surgical depending on the patient's symptoms and diagnosis. As anovulatory bleeding is one of the most common causes, hormonal therapy is the first approach after intra uterine pathology has been excluded. NSAIDs : These are thought to be menstrual blood loss through the inhibition of endometrial prostaglandins (PGE2 alpha and PGF2 alpha). Mefanamic acid, Tranexamic acid have been used with varying degree of success. HORMONES : Although progesterone only or estrogen progestin combination treatment of irregular or dysfunctional bleeding is common, no randomized controlled trials to demonstrate their efficacy in this setting exist. Progestin only regimens such as medroxyprogesterone acetate (MPA) have been shown to reduce both the amount and duration of uterine bleeding in anovulatory women. Specifically, MPA 10 mg per day for 10 to 14 days every month is effective in controlling unpredictable anovulatory bleeding. Progestins are able to induce a secretory transformation in otherwise estrogen stimulated proliferative endometrium, and they are effective in allowing a withdrawal bleed for women with thickened endometrial
54
9

linings that are commonly seen in anovulation.

10

Oral Contraceptives in low risk premenopausal women with hormone related symptoms who are not using any form of contraception, modern low dose (<35 g ethinyl estradiol) oral contraceptives offer many advantages with minimal risk (59). New formulations contain as little as 20 g of ethinyl estradiol and 1 mg of norethindrone acetate. In addition to preventing undesired pregnancies, these formulations are associated with a high degree of menstrual regularity and can be used to treat symptoms associated with a high degree of menstrual regularity and can be used to treat symptoms associated with relative estrogen deficiency. The use of oral contraceptive until menopause has been found to be safe in women with no risk factors for cardiovascular disease. Before starting the administration of oral contraceptives in this age group, patients should be free of the following risk factors : hypertension, hypercholesterolemia, cigarette smoking, previous thromboembolic disorders, cerebral vascular disease, or coronary artery disease. The levonorgestrel releasing intrauterine device (IUD) is able to release 20 mcg of levonorgestrel per day to act locally at the level of the uterus. This system has been shown to be effective for endometrial protection during estrogen therapy. In patients with dysfunctional uterine bleeding, this progesterone IUD was found to be equally effective compared with endometrial resection after a 1 year follow up. In a population of women with menorrhagia, levonogestrel releasing IUDs compared similarly to hysterectomy but at a significantly lower cost.
12 11

SURGICAL METHODS : Hysrerectomy is the second most common operative procedure after caesarean section among reproductive aged women. The average age at hysterectomy is 44.5 with same regional variation. Although it is a very effective surgical procedure, hysterectomy is associated with a certain degree of morbidity and cost. Prior to recommending a hysterectomy, an adequate preoperative evaluation must include endometrial sampling and an adequate trial of hormonal therapy to control the bleeding. The Maine Women's Health Study analysed close to 600 women with these complaints and found that patients with abnormal uterine bleeding who were treated initially with nonsurgical management (cyclic progestins, oral contraceptives, or nonsteroidal antiinflammatory medicines) had a statistically significant improvement in symptoms through one year of follow-up. However, close to 25 % went onto have a hysterectomy after the year of nonsurgical management and noted highly effective relief and improvement in quality of life as measured by surveys.
13

ENDOMETRIAL ABLATION : Surgical alternatives to hysterectomy offer less radical and potentially more cost effective
55

methods to treat menorrhagia. Endometrial ablation using lasers or electro cautery or thermal balloon ablation has been used and demonstrates an amenorrhoea rate of upto 50 % and patients satisfaction close to 90 %. A large prospective cohort study noted that 80 % of endometrial ablation patients needed no further surgery, whereas 9% underwent hysterectomy within 5 years of the initial procedure.14 However, endometrial ablation offers immediate results and has been shown to be effective on its own, without the need for pretreatment in a benign setting. SUMMARY: The management of benign symptoms, diagnosing and treating serious pathology is a complex balance when viewed in the light of the vast treatment options available. A detailed history and appropriate testing remain the principal starting point to providing better care for a woman during her reproductive aging process.

PERIMENOPAUSAL BLEEDING WORKUP AN ALGORITHM

Anovulatory bleeding, Ut. Fibroids, polyps, endometrial hyperplasia, endometrial carcinoma.

Abnormal Bleeding

Menstrual History

Laboratory Work Up Hb %, PCB, Complete Haemogram, FSH-E2, T3, T4, TSH

Trans Vaginal Ultrasound I Hysterosonography

Endometrial Biopsy (Pipelle)

Simple Hyperplasia or normal Pathology

Tissue Insufficient

Complex Hyperplasia or Malignancy

Hysteroscopy Hysteroscopy & Curettage

Abnormal Normal

Non Hormonal / Hormonal Treatment Repeat Endometrial Biopsy In 6 months for Hyperplasia

Simple Hyperplasia

Atypical Hyperplasia or Malignancy

Hysterectomy

56

Bibliography : 1. Akas Jain and Nanette Santoro Endocrine Mechanisms and Management for Abnormal Bleeding due to Perimenopausal Changes Clinical Ostetrics & Gynaecology 2005 ; Vol. 1, No. 4, 419 435. Brambilla DJ, McKinlay SM, Johannes CB, Defining the perimenopause for application in epidemiologic investigations. Am J Epidemiol. 1994 ; 140 : 1091 1095. William W. Hurd Menopause Novaks Gynaecology Text Book 12th Edition ; Chapter 29 : 981 1011. Fraser IS, McCarron G, Markham R. A Preliminary study of factors influencing perception of menstrual blood loss volume. Am J Obstet Gynaecol. 1984 ; 149 : 788 793. Santoro N, Brown JR, Adel T, et al. Characterization of reproductive hormonal dynamics in the perimenopause, J Clin Endocrinol Metab. 1996 ; 81 : 1495 1501. Belsey Em, Pinol AP. Menstrual bleeding patterns in untreated women. Task Force on Long Acting Systemic Agents for Fertility Regulation. Contraception. 1997 ; 55 : 57 65. Stovall TG, Photopulos GJ, Poston WM, et al. Pipelle endometrial sampling in patients with known endometrial carcinoma. Obstet Gynaecol. 1991 ; 77 : 954 956. Goldstein SR. Use of ultrasonohysterography for triage of perimenopausal patients with unexplained uterine bleeding. AM J Obstet Gynaecol. 1994 ; 170 : 565 570. Jennings JC. Abnormal uterine bleeding Med Clin North Am. 1995 ; 79 : 1357 1376.

2. 3. 4. 5. 6. 7.

8. 9.

10. Bishop PM, Cabral de Almeida JC. Treatment of functional menstrual disorders with norethisterone. Br Med J. 1960 ; 5179 : 1103 1105. 11. Marshall LM,. Spiegelman D, Barbieri RL, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynaecol. 1997 ; 90 : 967 973, 12. Hurskainen R, Teperi J, Rissanen P, et al. Quality of life and cost-effectiveness of levonogestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia : a randomized trial. Lancet. 2001 ; 357 : 273 277. 13. Carlson KJ, Miller BA, Fowler FJ Jr. The Maine Women's Health Study : I. Outcomes of hysterectomy. Obstet Gynaecol. 1994 ; 83 : 556 565. 14. O'Connor H, Magos A. Endometrial resection for the treatment of menorrhagia. N Engl J Med. 1996 ; 335 : 151 156.

57

HEREDITARY ANEMIAS
Dr. Hema Divakar Divakars speciality hospital Bangalore India

Anemia is the commonest medical disorder in pregnancy having varied incidence, etiology and degree of severity in different populations with the prevalence ranging between 35 to 75 % in developing countries. (ref 1, 2). Anemias can be classified according to clinical, morphologic or etiologic factors and characteristics. There are advantages to each system and they mesh with each other. Clinical classification allows the physician to adjust the pace of diagnosis and treatment according to the severity of the patient's condition. Morphologic classification, based on examination of peripheral smear, is the most common way to arrive at a specific diagnosis and a good way to proceed in a cost effective search for the source of anemia. Etiologic classification describes hereditary anemias and acquired anemias. This article will detail the HEREDITARY ANEMIAS. These are due to intrinsic defects in the erythrocyte membrane, glycolytic pathway, glutathione metabolism or haemoglobin molecule. Since iron deficiency anemia is the most common, many clinicians would initiate therapy and reevaluate in one month. If anemia fails to improve, a more intensive clinical and laboratory evaluation is justified. Thalassemia is hereditary condition which can be aggravated by pregnancy. It results when an insufficient amount of hemoglobin is produced to fill the red blood cells. The unbalanced synthesis of hemoglobin leads to premature RBC death and results in severe anemia. This is being detailed in a separate article. Sickle cell anemia is a hereditary birth defect. It is a recessive, hereditary, familial hemolytic anemia where abnormal hemoglobin types (SS or SC) produce recurrent attacks (crisis) of pain and fever. In sickle cell disease though, this hemoglobin becomes moon (or sickle) shaped, and cannot fit through the blood vessels properly. As a result, people with sickle-cell anemia don't get enough oxygen delivered throughout their bodies causing extreme fatigue.
58

These sickle-shaped cells can also clog the blood vessels, causing tissue damage, organ failure, and even death. Sickle cell anemia is most common among African Americans, with about 2 million African Americans carrying the sickle cell trait. People who carry the sickle cell gene but do not have sickle cell anemia are said to have "sickle cell trait". If both partners carry sickle cell gene - it is passed on to the child. If only one partner carries the gene , the offspring will be a carrier. Amniocentesis can be performed between the 14th and 16th week of pregnancy to determine if the fetus has sickle cell anemia. Sickle cell symptoms tend to vary from person to person. They also tend to increase in severity as you age. Common sickle cell symptoms include: v pain in the stomach, legs, and arms v chest pain v jaundice v extreme fatigue v growth problems v frequent illness and infection Possible complications include: v Vision Loss: Sickle-shaped hemoglobin cells can block the tiny blood vessels surrounding the eyes, causing vision loss. v Organ Damage: Blocked blood vessels can cut off blood and oxygen supply to key organs, including the liver, kidney, and spleen. v Stroke: Blocked blood vessels can prevent oxygen supply to the brain, causing a stroke. v Acute Chest Syndrome: People with sickle cell anemia are highly susceptible to infection. v Acute chest syndrome is similar to pneumonia and can cause fever, pain, and breathing problems. Laboratory Studies show reticulocytosis except during aplastic crisis. The peripheral smear shows sickle cells, holly leaf cells or Howell Jolly bodies. The Hb electrophoresis shows varying amounts of Hb S and Hb F . Treatment: There is no treatment for sickle cell anemia.

59

Common management includes: v penicillin injections to prevent and fight infections v pain medications v folic acid supplements, to help grow new red blood cells v blood transfusions, to increase the number of healthy red blood cells v bone marrow transplants to help the body create healthy red blood cells Transfusions are required to keep the hematocrit level at least 30%. Nagel and co workers (3) reported that recombinant human erythropoietin can stimulate the F reticulocyte responses In a randomized trial , Charache and colleges reported that hydroxyurea therapy ameliorated the clinical course of the disease.(4) Perrine and collegues reported the response of the patients to infusions of arginine butyrate (5) A remarkable trial (6) of zinc supplementation in the prevention of vaso-occlusive episodes and a significant reduction in the infective episodes is encouraging. Pregnancy outcomes in sickling syndromes are highly variable and needs extensive expertise for procedures like partial exchange transfusions. Hb C disease has Hb C In the heterozygous state, illness is rare unless associated with sickling. In the homozygous state, relatively insoluble Hb C crystallsises in the oxy haemoglobin state, causing the red cells to become rigid. Fragmentation and loss of membrane material leads to the presence of microspherocytes on the peripheral smear. Prenatal diagnosis is needed only if SC disease (sickle and Hb C) is suspected. Symptoms are rare and maternal and perinatal outcomes are good. Hb E disease has Hb E A specific gene defect in the DNA for Hb E results in abnormal splicing leading to defective chain synthesis. Hence it resembles thalasemmia intermedia. Hb E trait affects 25 % of Southeast Asian women (7) and has been reported in 50 % of an isolated population in India.(8) Growth restriction and fetal wastage can occur in those with homozygous Hb E (9) (10). Hereditary spherocytosis Hereditary spherocytosis is the commonest form of haemolytic anaemia seen in northern Europe and it is important to know that most children who have mild disease, can live a normal life, and do not require splenectomy. It is one specific familial hemolytic disorder characterized by marked heterogeneity of clinical
60

features, ranging from an asymptomatic condition to fulminant and extremely serious hemolytic anemia. The most common characteristic of hereditary spherocytosis is one structure called the microspherocyte- the sphere-shaped red blood cell, which is caused by loss of membrane surface area, and an abnormal osmotic fragility in vitro. Because the spherocytes have a smaller surface area through which oxygen and carbon dioxide can be exchanged- they perform adequately to maintain healthy oxygen supplies. However, they have a high osmotic fragility -when placed into water, they are likely to burst.

Frequency of the condition: Hereditary spherocytosis is the most common of the hereditary hemolytic anemias among people. Researches done in the past have proven that, in the United States, the incidence of the disorder is approximately 1 case in 5000 people. It is proven that this condition is usually transmitted as an autosomal dominant trait, and the identification of the disorder in multiple generations of affected families is the rule. An autosomal recessive. The The disease is also encountered worldwide, but its incidence and prevalence in other groups are not established clearly. Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. Anemia usually is mild to moderate; however, sometimes it is very severe and sometimes it is not present. Splenomegaly is the rule, and palpable spleens have been detected in more than 75% of affected subjects. Severe hemolytic anemia requires red cell transfusions.

Mechanism of the condition: The most important thing there is to know about this condition is that the defects in hereditary spherocytosis are in the red cell membrane. This is because the proteins essential for the integrityof the membrane structure lie immediately under the lipid layer. It is proven that different genes code each of these proteins, thus hereditary spherocytosisis a heterogeneous disorder..

61

Symptoms of the condition: Every patient should know that the spleen's hemolysis results directly in varying degrees of anemia and hyperbilirubinemia. These two conditions can result in symptoms of: v Fatigue v Pallor v Jaundice Chronic symptoms include anemia and splenomegaly. Lab Studies: The classic laboratory features of this type of anemia include minimal or no anemia, reticulocytosis, an increased mean corpuscular hemoglobin concentration (MCHC), spherocytes on the peripheral blood smear, hyperbilirubinemia, and abnormal results on the osmotic fragility test. Other biochemical changes of hemolysis also are also present, including: v increased lactate dehydrogenase (LDH) v increased unconjugated bilirubin v decreased serum haptoglobin v an increase in MCHC The treatment of this type of anemia involves pre-splenectomy care, splenectomy, and postsplenectomy complications. Problem is that children with severe hyperbilirubinemia caused by this type of anemia are at risk for kernicterus, and these infants should be treated with phototherapy and exchange transfusion as clinically indicated. Iron supplementation: Researches are showing that iron supplementation supports the increased production of red blood cells, but in longstanding cases in which patients have taken supplemental iron or received numerous blood transfusions; iron overload may be a significant problem, being a potential cause of cardiomyopathy and liver disease. The hereditary stomatocytosis syndromes The hereditary stomatocytosis syndromes and allied disorders are usually transmitted in an autosomal dominant pattern, although apparently sporadic cases have been reported. Penetrance is variable, with significant disparity in clinical symptomatology between affected individuals in the same kindred.

62

Many patients present with hemolytic anemia in the neonatal period, but others are asymptomatic throughout their lifetime. Aplastic crises associated with parvovirus and other infections have been reported. An unusual characteristic of the stomatocytosis syndromes is a predisposition to severe lifethreatening thrombosis after splenectomy. Enzyme deficiency anemias G6PD deficiency X linked recessive trait high prevalence G6PD is the key enzyme in the hexose mono phosphate shunt. Lack of G6PD lessens the reducing power of the erythrocyte.producing rigid membranes and Henz bodies. Diagnosis is by exclusion Treatment includes Vit E and Folic acid supplementation. Prognosis is good. PK pyruvate kinase defeciancy and G6PI glucose 6 phosphate isomerase deficiencies show symptoms of anemia, jaundice and splenomegaly. Fetal hydrops and spontaneous abortions are associated with enzyme deficiency anemia. Conclusions : Though iron deficiency anemia is a common problem, there are other non-nutritional anemias that may be seen. Some of these may manifest for the first time in pregnancy. Although these conditions are rare, it is important for the obstetrician to recognize these and initiate appropriate interventions, if and when required. References v Die jamaron FME, Abdulaziz A Anemia in pregnancy Int J Glyrol obst -1999 v Shehwartz WJ; Tumanu- Iron Deficiency anemia in pregnancy Clin .obst Gynecol -1993 v Nagel RL ,Shah M, et al. F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study.Blood-1993 v Charache S, Terrin ML,Moore RD,et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. New England J of Medicine-1995 v Perrine SP,Ginder GD,Faller DV,et al.A short term trial of butyrate to stimulate fetalglobin-gene expression in the beta-globin disorder. N Eng J Med-1993

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v Gupa VA,Chaubey SB.Efficacy of Zinc therapy in prevention of crisis in sickle cell anemia:a double bind ,randomized controlled clinical trial.J Assc Physicians India-1995 v Pravatmuang P,Tilokhus M, Suannum M,Chaipat C.Phitsanulok population:the highest incidence of hemoglobin E in the northen provinces of Thiland and PND Counseling.Southeast Asian J Trop Med Public Health-1995 v Deka R,Fertility and hemoglobin genotypes:a population study in upper Assam.Hum Genet-1981 v Ong HC.Maternal and fetal outcome associated with hemoglobin E trait and hemoglobin E disease. Obstet Gynecol-1975 v Belgir RS. Reproductive profile of mothersin relation to hemoglobin E genotypes.Indian J Pediatr_1992

64

ACQUIRED HEMOLYTIC ANEMIAS

Biliangady Harsha N. MD Associate Professor Kempegowda Institute of Medical Sciences Sonologist 'NORTH STAR' Women's Hospital, Bangalore Definition: Hemolytic anemias develop from an increase in the rate of red cell destruction. The normal life span of red cells is 100 - 120 days; in hemolytic anemias this is shortened by varying degrees and may be a few days only in severe cases. Classification: There are two basic causes of red cell destruction 1. Intracorpuscular (Intrinsic) i.e. abnormality of the red cells which results in premature destruction i.e. if these patients are transfused with normal red cells, the transfused cells, have a normal life span. The condition is mainly congenital due to an abnormality in the red cell itself i.e. in the membrane itself. An Extracorpuscular (Extrinsic) i.e. development of an abnormal hemolytic mechanism. Normal compatible red cells are prematurely hemolysed. Whereas red cells from these patients when transfused to a normal individual will have a normal life span. In other words these individuals have normal red cells but have developed an abnormal hemolytic mechanism i.e. there is an acquired hemolytic process or more accurately an auto immune acquired hemolytic anemia.

2.

AUTO IMMUNE ACQUIRED HEMOLYTIC ANEMIA (AIHA) AIHA is a group of disorders due to formation of antibodies against the antigens on the surface of the patients own red cells, i.e. they act as auto antibodies. The antibodies are most often IgG or less often IgM or IgA. Some are known to bind complement also. These auto - antibodies may form as a result of breakdown of T cell regulation of B cells with the emergence of a hostile clone of immunocytes. Or, a change in the structure of the surface antigen on red cell is recognized as 'non self' by the immune system. In reality the pathogenesis of AIHA is not really known. AIHA is not a rare disorder and occurs in all grades of severity ranging from a chronic mild asymptomatic condition to a rapidly acutely fatal state. CLASSIFICATION OF AIHA: AIHA is classified depending upon the 1. 2. The temperature at which the antibody reacts with the red cells into warm and cold antibody types (table1). According etiology in to idiopathic and secondary types (table2).

Warm AIHA: Seen more frequently in adults than in children and the idiopathic form is seen more often in women over the age of forty. The most important causes of secondary AIHA are
65

chronic lymphocytic leukemia; malignant lymphoma and systemic lupus erythematosus (SLE). Some drugs like methyldopa are known to cause secondary AIHA. Its use as an antihypertensive is now rare but is still popular in the management of pregnancy induced hypertension (PIH). Clinical Features: An insidious onset with features of anemia is usual. In secondary AIHA the underlying disease is ongoing at the time of hemolysis. Mild to moderate jaundice is present but is persistently absent in about 25% of the patients. The spleen is always enlarged and is nearly always palpable, but rarely beyond the limits of the umbilicus. A very large spleen suggests a chronic lymphocytic leukemia or malignant lymphoma. Moderate hepatomegaly is present but lymphnode enlargement does not occur in idiopathic cases though it is a common finding in secondary AIHA. Hemoglobinuria is occasionally seen. In young children and some adults the onset is sudden following a minor viral or bacterial infection. Intravascular hemolysis is seen as a hemoglobinemia and hemoglobinuria; oliguria and anuria are rare. Hemolysis normally stops on its own and is followed by complete recovery. Death occurs rarely when the condition is severe. Blood Picture: The typical feature is one of reticulocytosis with spherocytosis and positive direct antiglobuilin test. Reticulocyte count ranges from 5 30 % but can be higher. Rarely reticulocye count may be normal or even reduced in an aplastic crisis . Spherocytosis is present in active disease as is evidenced by a raised osmotic fragility and if mild this may be the only clue as it is unlikely to appear on a blood film. A mild increase in MCV is common . Polychromatic macrocytes are prominent in a blood film with a high reticulocyte count. Leucocytosis is seen in acute severe case, and counts of 20 30 x 109/L or more are quite common in chronic moderate cases the count is often normal or very rarely moderately reduced. Platelet counts are mostly normal or sometimes low enough to cause purpura. Serum bilirubin is between 17 50mol/L. Erythrocyte sedimentation rate (ESR) is markedly elevated in the active phase returning to normal during remission. Immunoglobulins are reduced in about 50% of the women the deficiency being IgA most commonly, but IgG and/or IgM deficiency or deficiency of all three are also seen. Blood drawn for routine examination shows mild agglutination in the collection tube and blood film. This is not prevented by drawing blood into pre warmed syringes at 37 C, representing red cells coated heavily with incomplete antibody. This should not be mistaken for the more intense agglutination of Cold Hemagglutinin Disease. Antibodies on the red cell surface: This is detected by positive direct antiglobulin testing using a broad - spectrum reagent. Monospecific reagents are more precise and it is found that 56% show a coating with IgG and complement C3, 35% have IgG alone and IgA and IgM. In SLE the red cell coating is almost always IgG and complement. With methyldopa induced hemolysis it is IgG alone . It is important to understand that there are numerous causes for a positive direct antiglobulin test besides AIHA. Methyldopa is an important cause for positive antiglobulin test even in the absence of active hemolysis. Diagnosis: Typical findings of hemolytic anemia including jaundice, splenomegaly,
66
2 o 1 1

reticulocytosis and an increased serum bilirubin with a positive direct antiglobulin test. 25% may not have jaundice. Bone marrow aspiration or a trephine biopsy is indicated and a careful search for evidence of leukemia, malignant lymphoma and megaloblastic red cells is made. Tests for SLE must be conducted, in acute cases. In children viral infections must be ruled out. Course and Prognosis: The course of the idiopathic form of the disease is variable and forecasting the outcome is difficult. Most patients respond initially to some form of treatment. In chronic disease hemolysis may continue for years, the disability depending upon the degree of anemia. No patient is cured if the antiglobulin test remains positive even if hemoglobin, reticulocyte count and serum bilirubin have returned to normal. A Mayo Clinic study on survival rates has found 91% and 73% at one year and ten years respectively . Treatment: In most adults and children with severe disease corticosteroids, blood transfusion and splenectomy form the key to management. Immunosuppression may be necessary for some. Corticosteroids: Induce prompt remission in about 80% of cases. The dose of prednisone varies from 60 80 mg/day to start with, and 5 15 mg/day maintenance to keep the hemoglobin at 11Gm%. Patients requiring more than 15mg of prednisone will be benefited by splenectomy. Corticosteroid therapy is deemed to have failed if there is no improvement after three weeks of treatment. Blood Transfusion: Is not necessary in moderate cases. In severe cases packed red cells are used to maintain hemoglobin levels and blood volume. The auto - antibodies on the red cell surface interfere with grouping and cross matching and this must be performed by an experienced transfusion specialist. Guidelines for transfusion in AIHA must be strictly followed . Splenectomy: Is reserved for 1. 2. Idiopathic cases not responding to adequate treatment with steroids and secondary AIHA not responding to treatment of the underlying cause. Patients requiring large doses of steroids to maintain adequate hemoglobin levels. Sometimes complete remission may not be achieved but at least the dose of steroid required is reduced. It is important to explore the abdomen for accessory spleens and ovarian dermoids. A histopathological examination of the spleen may be the first clue to a malignant lymphoma. Immunosuppressive Therapy: Generally reserved for patients that do not respond to splenectomy and are requiring high doses of steroids. The drugs used are Azathioprine 2.0 2.25 mg daily or Cyclophosphamide 1.5 2.0 mg daily. Neutrophil count must be carefully monitored and long term Azathioprine therapy is sometimes associated with the development of malignant lymphoma . All patients with continuing hemolysis must get 5.0 mg of Folic acid/day. Treatment for secondary AIHA is as in idiopathic AIHA with concurrent management of the
5 4 3

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causative disorder. When AIHA develops in a patient with a previous H/O malignant lymphoma or other neoplasm a thorough check for recurrence must be made. COLD ANTIBODY AUTO IMMUNE ACQUIRED HEMOLYTIC ANEMIA AIHA due to cold antibodies that react with red cells at temperatures less than 37 C, are less common than the warm antibody type. Two forms are recognized 1. 2. Cold Hemagglutinin Disease (CHAD) characterized by antibodies that react with red cells at low temperatures. Paroxysmal Cold Hemoglobinuria (PCH) characterized by episodes of acute hemolysis due to auto - antibodies that act primarily on red cell lysins at low temperatures.
o

Both CHAD and PCH can be idiopathic or secondary to an underlying disease. Cold Hemagglutinin Disease: Idiopathic CHAD is seen in adults over 50 years of age. It is rare in children with most patients running a chronic course. Unlike warm AIHA, CHAD is equally distributed between men and women. The secondary form occurs as a rare complication of SLE, malignant lymphoma and chronic lymphocytic leukemia, or a transient anemia secondary to infectious mononucleosis (Table 2). Clinical Features: In idiopathic CHAD and in CHAD associated with SLE, malignant lymphoma or chronic leucocytic leukemia the onset is insidious. Two patterns are seen depending on the thermal range of the antibodies. Some experience acute intravascular hemolysis and hemoglobinuria in winter and have normal hemoglobin in summer. Others are well compensated with mild or moderate chronic hemolytic anemia which worsens only slightly in winter. Agglutination occurs in the peripheral cooler parts of the circulation causing varying extents of microvascular obstruction and signs of cold sensitivity ranging from Raynaud's phenomenon, acrocynosis and rarely peripheral gangrene. These phenomena are seen most often in winter and are unlikely to be seen in temperate climates. Very rarely a terminal complication of CHAD can be a malignant lymphoma, but more frequently CHAD develops in patients with pre existing lymphoma . Post infectious CHAD has an acute onset during the second or third week of infection. Acute intravascular hemolysis, jaundice and splenomegaly are seen. Cold sensitivity is usually not seen and hemolysis takes up to 2 3 weeks to resolve. Blood Picture: Picture of anemia with red cell agglutination, reticulocytosis and a positive direct antiglobulin test. Red cell agglutination is an outstanding feature. This picture is seen on films prepared from capillary blood or blood collected into an anticoagulant and is often seen macroscopically in the collection tube. Agglutination can be prevented by using pre warmed syringes and slides kept at 37oC. Hemoglobin is rarely below 8g/dl. Spherocytosis is less marked
68
7 6

than in warm AIHA. Reticulocyte count is only mildly increased. Polychromatic macrocytes and occasional nucleated red cells are seen. White cell count and platelets are normal. Serum bilirubin is only mildly raised and plasma hemoglobin appears only during active disease, but hemosiderin is seen in the urine during both active and quiescent phases. Red cell agglutinates interfere with the functioning of automated counters giving falsely high MCV. Serum and red cell folate might be reduced. Immunology: Most cases of CHAD are caused by an auto - antibody referred to as anti I. This anti body reacts with the I antigen found on the red cell surface of all adults but not fetal RBC. This is a complete antibody which is inactivated at 37 C but agglutinates red cells with increasing strength as the temperature drops towards 4 C. The lytic activity of this antibody is much less compared to that of the Donath Landsteiner anti body of paroxysmal hemoglobinuria. The anti I antibodies of both idiopathic and secondary CHAD are IgM type with light chains. Serum IgM levels are elevated above 6 g/L and IgG and IgA are normal. The anti I antibody of CHAD secondary to mycoplasma infection is also an IgM, but is polyclonal consisting of and light chains. The direct anti globulin test is positive if blood is drawn and kept at 37 C and washed in warm saline before testing. The positive test is due to the presence of complement C3d on the red cell surface. Prognosis and Treatment: The idiopathic disease progresses slowly and many patients remain relatively well especially when upper thermal ranges of the antibody does not exceed 28 C. Protection from cold or a shift to temperate climate is often enough. Corticosteroids and splenectomy are rarely effective. Chlorambucil is useful and reduction of IgM in the serum is seen. When transfusion is necessary pre warmed concentrated red cells are transfused keeping the patient warm. Paroxysmal Cold Hemoglobinuria (PCH): A rare disorder seen as attacks of hemolysis with hemoglobinuria on exposure to cold. The condition develops due to the development of a cold auto - antibody with strong lytic activity. The blood shows a characteristic bithermic cold hemolysin that is demonstrated by the Donath Landsteiner test. The principle of the test is that the hemolysin in the patient's blood attaches to sensitized red cells when chilled and then hemolysed by complement when warmed to 37 C. This cold hemolysin is a complement binding IgG antibody having anti p blood group specificity. Paroxysmal Nocturnal Hemoglobinuria: This rare disorder is associated with a chronic hemolytic anemia and intermittent hemoglobinuria. The abnormality is an acquired defect of the red cell membrane making the cells unusually sensitive to lysis by the complement of normal serum. Three cell lines of red cells have been detected in PNH ; two populations of intermediate and extreme sensitivity to complement lysis and a third resistant population.
69
8 o o o o o

Appears usually between 30 40 years and affects men and women equally. Hemoglobinuria is seen in all patients and is related to sleep irrespective of sleeping time. Characteristically night urine or the first morning sample is colored. Hemosiderinuria is always present and at autopsy renal tubules are laden with hemosiderin. Red cells are not found in the urine. Blood picture: Shows anemia of varying intensity. Moderate macrocytosis, polychromasia and moderate leucopenia are observed. Reticulocytes are increased but not to the expected extent for the anemia present. Diagnosis: This is made by the intermittent hemoglobinuria and presence of hemosiderin in urine. The condition should be suspected in patients with refractory anemia. Showing a pancytopenia, reticulocytosis or if a H/O transfusion reaction is present. Treatment: No specific treatment is available; management is mostly supportive with concentrated red cells as transfused red cells have a normal life span. Oxymethalone 10 -50 mg and androgens can be used. Splenectomy is of no value.
9

Hemolytic Anemia Due To Drugs and Chemicals: Many drugs cause hemolysis and they fall into three categories. 1. 2. 3. Those that have a direct toxic action on the red cells, hemolysis is dose related and occurs in most normal subjects provided that sufficient dose of the drug is administered. Those that cause hemolysis as a result of a hereditary metabolic abnormality of the red cells. Those that cause hemolysis by an immunological mechanism (Table 3). TABLE 1. WARM AND COLD ANTIBODIES IN AIHA WARM COLD AIHA CHAD Immunoglobulin Class Optimal reaction temperature Antibody specificity Immunochemical characteristics Serological behavior in vitro Protein on red cell IgG 37 C Often anti Rh Polyclonal
o *

PCH IgG

IgM 0-4 C Anti -I or anti - I

o

0-4 C Anti - P

Monoclonal Polyclonal Bipahsic hemolysin C 100%

Incomplete Agglutinin IgG 35% IgG +C56% C 9% C 100%

Legend: * Cold Hemagglutitnin Disease Paroxysmal Cold Hemoglobin Uria

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TABLE : 2 CLASSIFICATION OF AUTO - IMMUNE ACQUIRED HEMOLYTIC ANEMIA Idiopathic 50% Secondary 50% Drugs: Methyldopa, mefenemic acid, L-dopa , procaine amide Infections: Mycoplasma pneumoniae, infectious mononucleosis, cytomegalovirus. Chronic lymphocytic leukemia Malignant lymphomas Systemic lupus erythematosus Other autoimmune diseases rheumatoid arthritis, chronic active hepatitis, myasthenia gravis, ulcerative colitis Miscellaneous - carcinoma, sarcoidosis, ovarian teratoma

TABLE : 3 DRUGS AND CHEMICAL AGENTS THAT MAY CAUSE HEMOLYTIC ANEMIA Drugs that regularly cause hemolytic anemia in normal subjects by direct toxic action Acetylphenylhydrazine Arsine Chloramine Copper Formaldehyde Naphthalene Para aminosalicylic acid Phenacetine Phenazopyridine Phenylhydrazine Potassium chlorate Resorcinol Sodium chlorate Sulphanilamide Sulphapyridine Sulphasalazine Sulphones

71

TABLE 3 DRUGS AND CHEMICAL AGENTS THAT MAY CAUSE HEMOLYTIC ANEMIA Drugs that cause hemolytic anemia in subjects with hereditary * metabolic abnormalities of the red cell ((principally G6PD deficiency) Sulphones Analgesics Acetanilide Antimalarials Pamaquin Pentaquin Primaquin Nitrofurans Nitrofurantoin Sulphonamides Sulphacetamide Sulmethoxazole Sulphanilamide Sulphapyridine Sulphasalazine Dapsone, Thiazole sulphone Miscellaneous Acetyphenylhydrazine Methylene blue Nalidixic acid Naphthalelne Niridazole Phenylhydrazine Trinitrotoluene

Drugs that cause hemolytic anemia by immune mechanism Immune Amidopyridine Antazoline Cephalosporines Chlorpropamide Cisplatin Dipyrone Erthromycin Insulin Isoniazid Nomifesine Para aminosalicylic acid Paracetamol Penicillin Phenacitin Quinidine Quinine Rifampicin
* In addition to these drugs, many of the agents causing hemolysis in large doses will cause hemolysis in small doses in G6PD defiant patients.
72

Sulphasalazine Stibophen Sulphonamides Teniposide Tetracycline Thiazides Thiopentone 13 Tolbutamide Triamterene Auto - immune L - dopa Mefenemic acid Procaineamide
* *

References 1. 2. 3. 4. 5. 6. 7. 8. Liestveld J.L. et al Variability of erythropoietic response in auto immune hemolytic anemia, Immune Hemolytic Anemia Methods in Hematology; Chaplin H (Ed): 987. Isis .P. Serological diagnosis and characterization of causative antibodies ; Immune Hemolytic Anemia, Methods in Hematology; Chaplin H (Ed): 1985. Silverstein .M.N et al Idiopathic Acquired Hemolytic Anemia, Survival in 117 cases; Arch Int Med: 129 (1972). Masouredis . S. P. et al Transfusion Management of auto immune hemolytic anemia, Immune Hemolytic Anemias Methods in Hematology Volume 12; 1985. Grunwald H.W. et al Acute leukemia and Immunosuppressive drug use, Arch Int Med , 139; 461: 1979. Crisp D & Pruzanski W. B cell neoplasms with homogeneous cold reacting antibodies (cold agglutinins); Am J Med 72; 915: 1982. Chaplin H. Lymphoma in primary cold hemagglutinin disease treated with chlorambucil, Arch Int Med ; 142: 2119 1982. Rosse W.F et al The population of red cells in paroxysmal nocturnal hemoglobinuria of intermediate sensitivity to complement lysis significance and mechanism of increased immune lysis Brit J Hemat: 28:181 1974 Rosse W.F Treatment of paroxysmal Nocturnal Hemoglobinuria, Blood; 60: 20, 1982.

9.

73

THALASSEMIA AND PREGNANCY

Dr. Narayanan. R. Malathi Memorial Hospital Bangalore The name thalassemia was coined at the University of Rochester in New York by the Nobel Prizewinning pathologist George Whipple and the professor of pediatrics William Bradford from the Greek thalassa for sea and -emia, meaning the blood. Thalassemia means "sea in the blood." But for the Greeks, the sea was the Mediterranean, so thalassemia also conveys the idea of the Mediterrranean in the blood. The reason that the gene for beta thalassemia is relatively common, among people of Italian and Greek origin is that parts of Italy and Greece were once full of malaria. The presence of thalassemia minor (like sickle cell trait in Africa) afforded protection against malaria, and therefore, this gene thrived. In India too, thalassemia is common in areas like the Kutch where malaria was once endemic. Thalassemia is the most common autosomal recessive genetic blood disorder that affects the production of hemoglobin, resulting in anemia. It is estimated that there are 200,000 thalassemics in the world among whom 5000 to 8000 are in India. About 100,000 babies worldwide are born with severe forms of thalassemia each year. Thalassemia occurs most frequently in people of Italian, Greek, Middle Eastern, Southern Asian and African ancestry. The two main types of thalassemia are called "alpha" and "beta," depending on which part of an oxygen-carrying protein in the red blood cells is lacking. Both types of thalassemia are inherited in the same manner. The disease is passed to children by parents who carry the mutated thalassemia gene. A child who inherits one mutated gene is a carrier, which is sometimes called "thalassemia trait." Most carriers lead completely normal, healthy lives. A child who inherits two thalassemia trait genes - one from each parent - will have the disease. A child of two carriers has a 25 percent chance of receiving two trait genes and developing the disease, and a 50 percent chance of being a thalassemia carrier. If one of the partners is a carrier the offspring has no risk of being a thalassemic, but 50% chance of being a carrier (Diagrams).

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Diagram depicting the transmission of Thalassemic gene to the offspring when both partners are carriers:

T
25% Thalassemic

TN

TN
50% Carrier

N
25% Normal
T - Thalassemia N - Normal TN - Carrier

Diagram depicting transmission of Thalassemic gene if one partner is a carrier:

TN

TN

NN

NN

50% Carrier

50% Normal
T - Thalassemia N - Normal TN - Carrier

Alpha Thalassemia: Most individuals with alpha thalassemia have milder forms of the disease, with varying degrees of anemia. The most severe form of alpha thalassemia, which affects mainly individuals of Southeast Asian, Chinese and Filipino ancestry, results in fetal or newborn death.
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Beta Thalassemia: The most familiar type of thalassemia is beta thalassemia. It involves decreased production of normal adult hemoglobin (Hb A), the predominant type of hemoglobin which begins soon after birth and continues until death. The globin part of Hb A has 4 protein sections called polypeptide chains. Two of these chains are identical and are designated the alpha chains. The other two chains are also identical to one another but differ from the alpha chains and are termed the beta chains. In persons with beta thalassemia, there is reduced or absent production of beta globin chains. There are two forms of beta thalassemia. They are thalassemia minor and thalassemia major (which is also called Cooley's anemia). Thalassemia minor: The individual with thalassemia minor has only one copy of the beta thalassemia gene (together with one perfectly normal beta-chain gene). The person is said to be heterozygous for beta thalassemia. Persons with thalassemia minor have (at most) mild anemia. This situation can very closely resemble that with mild iron-deficiency anemia. However, persons with thalassemia minor have a normal blood iron level (unless they are iron deficient for other reasons). No treatment is necessary for thalassemia minor. In particular, iron is neither necessary nor advised. Thalassemia major (Cooley's anemia): The child born with thalassemia major has two genes for beta thalassemia and no normal beta-chain gene. The child is homozygous for beta thalassemia. This causes a striking deficiency in beta chain production and in the production of Hb A. Thalassemia major is, therefore, a serious disease. At birth the baby with thalassemia major seems entirely normal. This is because the predominant hemoglobin at birth is still fetal hemoglobin (Hb F). Hb F has two alpha chains (like Hb A) and two gamma chains (unlike Hb A). It has no beta chains so the baby is protected at birth from the effects of thalassemia major. Anemia begins to develop within the first month after birth. It becomes progressively more and more severe. The infant fails to thrive and often has problems feeding (due to easy fatigue from lack of oxygen, with the profound anemia), bouts of fever (due to infections to which the severe anemia predisposes the child) and diarrhea and other intestinal problems. Without treatment, the spleen, liver and heart soon become greatly enlarged. Bones become thin and brittle. Heart failure and infection are the leading causes of death among children with untreated thalassemia major. The use of frequent blood transfusions and antibiotics has improved the outlook for children with thalassemia major. Frequent transfusions keep their hemoglobin levels near normal and prevent many of the complications of the disease. But repeated blood transfusions lead to iron overload that can damage the heart, liver and other organs. Iron chelators can help rid the body of excess iron, preventing or delaying problems related to iron overload.

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Thalassemia and Pregnancy: Although fertility is reduced in a woman with transfusion dependent beta thalassemia, pregnancy may be possible in some women. A few cases have been reported in literature. It is necessary for the obstetrician to involve in the management, a medical team consisting of hematologist, perinatologist and a genetic counselor. Because of the physiological changes in pregnancy, the heart, liver, spleen and the endocrine system are particularly vulnerable. Anemia becomes more pronounced and the requirement for transfusion increases. During pregnancy, the enhanced maternal nutritional needs must be taken care of and multivitamins are to be administered. But, iron should be avoided because of the concern of iron overload. Preconceptional administration of folate, which must be continued at least until the 10th week of pregnancy is important to facilitate cell division. Vitamin C in the dose of 100-150 mg helps in removal of iron. Further, thalassemic women are more at risk to develop insulin dependent diabetes during pregnancy. Maternal and fetal morbidity may also result from medications used and infections. Genetic counseling is essential for assessment of fetal risk and to explain to the mother the role of genetic testing in pregnancy. In a population based study conducted in Israel, Sheiner et al observed that oligoamnios and fetal growth restriction were significantly associated with -thalassemia minor. No significant differences were noted regarding perinatal outcomes such as birth weight, low Apgar scores, congenital malformations, or perinatal mortality. Patients with -thalassemia minor were more likely to have cesarean deliveries than were the nonthalassemic parturients (16.9% and 12.2%, respectively). However, while controlling for possible confounders such as IUGR, oligohydramnios, and previous cesarean delivery, with another multivariate analysis with cesarean delivery as the outcome variable, -thalassemia minor was not found as an independent risk factor for cesarean delivery. They concluded that the course of pregnancy of patients with thalassemia minor, including perinatal outcomes, is favorable. Because higher rates of IUGR were found, they recommended closer fetal surveillance for early detection of IUGR. Screening and genetic testing for haemoglobinopathies: Advances in genetic research that allow precise identification of mutations of the Hb genes make the process of identifying couples at risk for having offspring with the hemoglobinopathies increasingly important. Although universal screening is not recommended, all pregnant women at the initiation of prenatal care are to be subjected to CBC counts with RBC indices. Taking relevant history is important and particular attention must be paid to Kutchi Lohanas, Gujaratis,Sindhis, Punjabis, Kojas and Marwaris and patients of Southeast Asian, Mediterranean, or African descent. These patients can be referred for Hb electrophoresis. Those patients who have anemia and reduced MCV (<80 m3) and normal iron study findings also must be referred for hemoglobin electrophoresis. High pressure liquid chromatography, if available is of additional
77

diagnostic value. The investigative profile of the thalassemic individual is more fully described in the chapter on investigation of anemia in this monogram. Test is offered to the partner of any carrier of hemoglobinopathies and any patient with elevated HbA2 (>3.5%) to assess the risk to the fetus. If both partners are identified as carriers, DNA-based tests are offered for the fetus. Tests for prenatal diagnosis of thalassemia now include polymerase chain reaction (PCR) of fetal DNA extracted from amniotic cells, of trophoblasts from chorionic villus sampling (CVS), and of erythroblasts obtained from cordocentesis. Typically, CVS is performed at 10 weeks of gestation to avoid limb reduction defects and cordocentesis is done after 19 weeks if confirmation is needed. In many hemoglobinopathies, including sickle cell disease and most beta-thalassemias, point mutations exist for which specifically designed oligonucleotide probes can be used, especially in combination with knowledge of the patient's ethnicity. For some thalassemias, performing indirect DNA testing by linkage analysis is still necessary. Efforts to reduce the risks to the fetus incurred with invasive tests such as amniocentesis, chorionic villus sampling, and cordocentesis have been made by acquisition of fetal cells from the maternal circulation using magnetic cell sorting; however, this procedure is not standard. This technique can only work in hemoglobinopathies in which the mutation has been identified because only a small amount of fetal cells can be purified. A fascinating advancement in prenatal diagnosis has been the development of a preimplantation genetic diagnosis (PGD). In 1999, a team of reproductive endocrinologists reported single-cell PCR and DNA analysis of embryos from a couple, both carriers for sickle cell disease, with transfer of the genetically healthy embryos and subsequent delivery of healthy twins. Preventive strategies: The preventive programs are based on molecular diagnosis in high risk population. Screening is carried out by testing blood indices and Hb chromatography antenatally and postnatally. PCR and direct sequencing of DNA are done whenever required. Premarital counseling plays a vital role. The incidence of thalassemia could be brought down if carriers are discouraged from marrying another carrier. If both partners are diagnosed to be carriers after marriage, they may be offered the option of donor insemination (AID) or adoption. However, it may not always be practical to avoid biological offspring. In such couple at risk, prenatal diagnosis and medical termination of pregnancy may be offered to prevent an affected offspring. Current Research on Thalassemia: Scientists are working on better ways to remove excess iron from the body in order to prevent or delay iron overload. They are developing and testing the effectiveness of oral iron-chelating drugs, which could greatly simplify treatment of this disease.

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Development of an effective form of gene therapy may some day offer a cure for thalassemia. Gene therapy may involve inserting a normal beta globin gene into the patient's stem cells, the immature bone marrow cells that are the precursors of all other cells in the blood. Another form of gene therapy may involve using drugs or other methods to reactivate the patient's genes for fetal hemoglobin. After birth, natural genetic switches "turn off" production of fetal hemoglobin and "turn on" production of adult hemoglobin. Scientists are seeking ways to activate these genetic switches so that they can make the blood cells of patients with thalassemia produce more fetal hemoglobin to compensate for their deficiency of adult hemoglobin. Initial studies of rare individuals with genetic traits that allow them to produce only fetal hemoglobin show that they are generally healthy, demonstrating that fetal hemoglobin can be a fine substitute for adult hemoglobin. Thalassemia has been cured using bone marrow transplants. However, this treatment is possible only for a small minority of patients who have a suitable bone marrow donor. The transplant procedure itself is still risky and can result in death. Improved bone marrow transplantation methods may lead to wider use of the technique as a treatment for thalassemia. Resources and References: 1. 2. 3. 4. Thalassemia.com irondisurders.org ghr.nlm.nih.gov Kilpatrick SS and Laros RK.1995.Thalassemia in Pregnancy.Clin. Obstet.Gynecol, 38(3):485-496. Savona-Ventura C and Bonello F.Obstet.Gynecol.Surv.994 Feb; 49(2):129-37. Sheiner E et al.Beta Thalassemia minor during Pregnancy.Obstet.Gynecol.2004; 103:1273-1277.

5. 6.

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Uncommon causes of Anemia

Dr. Latha Venkataram, FRCOG Consultant Maiya Hospital Bangalore
Special problems in Pregnancy
Splenectomy not advisable in pregnancy

Cause
Enlarged spleen (idiopathic)

Mechanism
An enlarged spleen traps and destroys too many red blood cells

Comment
Symptoms tend to be mild; often an enlarged spleen reduces the number of platelets and white blood cells

Treatment
Treatment is aimed at the disorder that has caused the spleen to enlarge. Sometimes the spleen must be removed surgically

Anaemia secondary to renal disease

CRF

Worsening of anaemia in pregnancy Erythropoietin not contraindicated Dialysis not contraindicated Anticoagulant prophylaxis since more prone for thromobosis Ferttility rate low. Abortions increased. MMR increased. Prone for thrombosis, infection, marrow aplasia in pregnancy.O.C.P contraindicated. Iucd contraindicated if granulocytes & platelets low Hyperhaemolytic & aplastic crisis can occur. Folic acid supplementation recommended Termination of pregnancy recommended. Aplasia can rapidly deteriorate Can cause severe stomach cramps and clotting in the large veins of the abdomen like hepatic or mesenteric and lower limb veins Corticosteroids relieve symptoms, but no cure is available. People with blood thrombosis need therapeutic doses of anticoagulant. Bone marrow transplantation may be needed long term Treatment is usually not needed, but severe anemia may require removal of the spleen

Paroxysmal Genetic mutation in haemopoietic nocturnal stem cells affecting the red cells, hemoglobinuria granulocytes, platelets. The immune system destroys red blood cells in a sudden (paroxysmal) way, not just at night Autosomal dominant red blood cells become misshapen and rigid, getting trapped and destroyed in the spleen

Hereditary spherocytosis

An inherited disorder that can also cause bone abnormalities, such as a tower-shaped skull and extra fingers and toes

Aplastic anaemiaIdiopathic, medications, infections, toxins. Pregnancy rarely induces aplastic anaemia. Spontaneous resolution might occur after delivery G6PD deficiency The G6PD enzyme is missing from red blood cell membranes. Without the enzyme, red blood cells are more likely to break apart

Heterozygous women may have severe anaemia. Folic acid supplementation recommended. May need transfusions

An x linked inherited disorder that almost always affects only males. About 10% black males and a smaller percentage of white people of Mediterranean origin have the disorder

Anemia can be prevented by avoiding the situations or substances (fever, diabetic crisis, aspirin, vitamin K, fava beans) that trigger it

Autoimmune haemolytic anaemia

Primary or secondary-drugs, infections, SLE, neoplasia. Pregnancy itself might cause haemolytic anaemia

Steroids to be continued Transfusion may be required Neonatal anaemia may occur Recurs in subsequent pregnancy if the condition appears in pregnancy

The obstetrician should be aware of the unusual anaemias which could complicate the pregnancies leading to high maternal and perinantal morbidity and mortality. Chronic Anaemia and Anaemias resistant to treatment in a women should be investigated further in coordination with a Hematologist. Pre pregnancy counseling is an important aspect of care. Management plans during pregnancy should be drawn with the involvement of hematologist. Though there is an extensive list of unusual forms of anemia, few of them relevant to pregnancy have been mentioned here.

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INVESTIGATIONS IN ANAEMIA WHAT?

WHEN? AND WHY? Dr.Jayanthy.T MD Asst. Professor, Dept. of OBG Kempegowda Institute of Medical Sciences, Bangalore. There are spectrum of investigations done in case of anaemia. Plan of investigations for anaemia is done 1. To confirm anaemia and assess severity of anaemia 2. To investigate for type of anaemia and cause for anaemia 1. Screening & Diagnostic tests: a. Haemoglobin estimation.(Hb) Normal values Men 14 18 gm/dl Women 12 16 gm/dl Pregnancy 10.5 11 gm/dl

b. Peripheral blood film examination c. Red cell indices Packed Cell Volume (PCV) Mean Corpuscular Volume (MCV) Mean Corpuscular Haemoglobin (MCH) Mean Corpuscular Haemoglobin conc (MCHC) d. Leucocytes and platelet count e. Reticulocyte count 2. Confirmatory Tests: a. Bone marrow examination. b. Biochemical tests. c. Special tests to diagnose specific conditions. Relevant Investigations specific to type of anaemia. IRON DEFICIENCY ANAEMIA 1. Hemogolobin Estimation: Reduced haemoglobin. It is a late manifestation. It is preceded by depletion of iron stores, then reduction in Serum Iron. Though Hb decrease is a late sign, it is a simplest and practical test 1 - 2% Normal values Women 35 45% Men 40 52% 75 90 fl 27 31pg 30 35 g/dl

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2. Peripheral Blood Smear: Microcytic, Hypochromic RBC's. Anisocytosis, Poikilocytosis, Target cells are seen. Reticulocytes may be normal or decreased. The differential diagnoses are Thalassemia and Pyridoxine deficiency anaemia. 3. Red Cell indices: PCV is decreased. MCV, MCH and MCHC are reduced. 3. Bone Marrow Examination: It may not be required to make a diagnosis of iron deficiency anaemia. However, when done it shows erythroid hyperplasia and micronormoblastic reaction. There is reduction or absent stainable iron depending on iron depletion. 5. Biochemical Tests: a. Serum ferritin is a first indicator of iron deficiency anaemia normal value is 15 300 g/dl. Here it may be < 12g/dl. b. Serum iron is reduced to < 30g/dl. Normal value 50 - 150g/dl. c. Total iron binding capacity (TIBC) is increased to 500g/dl and TIBC saturation may be < 15%. Normal value is 250 450 g/dl. d. Red cell protoporphyrin level it is a sensitive indicator of iron deficient erythropoiesis. It may be increased to 100 g/dl. Normal is 20 - 40g/dl. e. Serum Transferrin Receptor (Tf R) is reliable for assessing celluar iron states. In iron deficiency there is a three fold increase in Tf R. Normal level is 4 9 g/dl. This, combined with serum ferritin gives a complete picture of iron status. f. Other tests to rule out chronic blood loss should be done after detailed history and examination for example urine microscopy for haematuria, stools for ova, etc. SIDEROBLASTIC ANAEMIA. It can be hereditary or acquired, and findings differ in both. a) Hereditary Hb is reduced Hypochromic microcytic cells are seen, some times a dimorphic picture. MCV and MCH are reduced. Serum iron is increased. TIBC shows complete saturation. Bone marrow shows ring sideroblasts, mature erythroblasts and increased stainable iron. b. Acquired 1. Hb is reduced.
82

1. 2. 3. 4. 5. 6.

2. 3. 4. 5. 6.

PBS dimorphic picture, target cells, stippled cells and siderocytes, Pelger Huet neuetrophils. MCV is increased but MCH is decreased. Serum Iron and ferritin is increased.

TIBC is decreased. Bone marrow shows hyperplastic and ring sideroblasts, Pappenheimer granules. MEGALOBLASTIC ANAEMIA Folic acid deficiency Hb decreased. PBS Macrocytes, anisopoikilocytes, Cabot'srings, tear drop cells, hypersegmented neutrophils (at least three cells having more then five nuclear segments), basophilic stippling, Howell Jelly bodies. In late stages there may be neutropenia and thrombocytopenia. When there is associated iron deficiency there may be many microcytic cells along with macrocytes c. MCV is more then 100fl. MCH is increased to more then 35pg but MCH is normal. d. FIGLU Test (Formiminoglutamic Acid) In folate deficiency FIGLU is increased in urine and it is non specific and not very useful. e. Bone marrow shows dyserythropoiesis, megaloblasts in erythroid series, myeloid /erythroid ratio falls to 1:1. Special tests: a. Serum folate levels It will indicate levels of folate for preceding few days only. It is transient and will alter with folic acid administration. Normal is more than 5ng/ml. b. Red cell folate levels Normal is 160 to 640g/l. Reduction in this is a better indicator of folate deficiency. 2. Vitamin B12 (Cobalamin) deficiency This may be a rare entity but when ever there are clinical features and folic acid levels are normal in megaloblastic anaemia, cobalamin deficiency should be suspected. Red cell indices, peripheral blood picture and bone marrow are similar to folate deficiency anaemia, but here folate levels are normal. Special tests: 1. Serum vitamin B12 assay : a.Microbiological assay using Euglena gracilis or Lactobacillus Leichmani. b.Radioisotope assay a. b.

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Normal is 200 to 900 pg/dl less then 100pg/dl indicates deficiency.. 2. Increased levels of both Serum Methyl malonic acid and homocystine. 3. Increased urinary excretion of Methyl malonic acid. 4. Radioactive vitaminB12 absorption test a. Radioactivity in faeces. b. Radioactivity in urine (Schilling test) c. Radioactivity in liver d. Radioactivity in whole body e. Radioactivity in plasma Schilling test is commonly done. This helps in knowing intrinsic factor deficiency. Megablastic anaemia is seen in various other conditions like chronic liver disease, rheumatoid arthritis etc. Depending on the clinical manifestations, specific investigations have to be done. 3. Dimorphic anaemia In India and other developing countries patients manifest multiple deficiencies like iron, folic acid, cobalamin, pyridoxine and other vitamins. In such cases there is a dual population of macrocytic and microcytic hypochromic RBC's. In some cases macrocytic hyprochromic cells are seen. 4. Haemolytic anaemia In Haemolytic anaemias haemolysis is a common feature. In most of the conditions, tests for haemolysis and findings are similar. Therefore tests common to all types of haemolytic anaemias is discussed first followed by specific investigations in each type of disorders. Evidences of haemolysis. Increased breakdown of haemoglobin causes a. Reduced haemoglobin - sometimes Hb may be normal. b. Hyperbilirubinemia. (unconjugated) c. Reduced plasma haptoglobin and haemopexin. d. Increased plasma LDH. e. Increased urinary urobilinogen. f. Increased reticulocyte count. Evidences of Intravascular haemolysis: a. b. c. Haemoglobinuria and haemoglobinemia. Haemosiderinuria. Methaemoalbuminemia.

The specific tests for each type of haemolytic anaemias is discussed further.

84

I. Thalassemia This is quite common in our country and is a differential diagnosis for microcytic hyprochromic anaemia. a. b. Reduced Hb. PBS Microcytic, hypochromic red cells. Moderate to severe anisocytosis and poikilocytosis ,nucleated RBC's, plenty of target cells, tear drop cells ,granular cytoplasmic inclusionbodies, polychromasia reticulocytosis ismarked and more than 10%

c. MCV and MCH is markedly reduced . MCHC is normal. d. Serum iron level is markedly increased. e. Serum ferritin is 300 to 3000 ng/dl. f. TIBC saturation is more than 70%. g. Bone marrow shows micronormoblastic reaction, erythroid hyperplasia, striking basophilic stippling and increased iron deposition and ring sideroblasts. Other Tests Decreased osmotic fragility Alkali denaturation tests This test is based on the factor that normal adult haemoglobin gets denatured when alkali is added but fetal haemoglobin is resistant and not destroyed. This test reveals increased HbF levels in thalassemia major. 3. Hb electrophoresis. In thalassemia minor, HbH is present in adults and Hb Barts in infants. Electrophoresis using starch agarose gel at PH 8.6 is useful in diagnosis, which shows increased HbF and HbA2. 4. Genomic study of DNA by Southern blotting of endonuclease is a very useful test. Prenatal diagnosis of Thalassemia is very useful. II. SICKLE CELL ANAEMIA: Hb reduced. PBS normochromic, normocytic cells, fragmented RBC's, anisopoikilocytosis, target cells and sickle cells are seen. Reticulocytosis is present. 3. MCV and MCH are normal. MCHC is increased. 4. Bone marrow shows erythroid hyperplasia. Other Tests: 1. 2. 3. ESR is decreased. Osmotic fragility is decreased. Sickling test is positive. It can be demonstrated by adding Sodium metabisulphite or ascorbic acid. Sickledex, a proprietary product is available. It detects HbS by precipitation of deoxygenated HbS. It is rapid and reliable.
85

1. 2.

1. 2.

4. 5. 1. 2. 3. 4. 5.

Life span study of RBC's shows decreased survival. Hb electrophoresis shows increased HbS. Hb is reduced. PBS Spherocytes lacking central pallor, reticulocytosis and thrombocytopenia is seen. MCV is normal, sometimes it may be decreased. MCH is normal. MCHC is raised. Increased osmotic fragility. cDNA Genomic DNA analysis for molecular diagnosis may be helpful.

II. HEREDITARY SPHEROCYTOSIS

III. HERDITARY ELLIPTOCYTOSIS 1. Haemoglobin is reduced. 2. PBS Ovalocytes or Elliptocytes are seen and constitute more than 50% of the cells. 3. MCV and MCH are normal. 4. Osmotic fragility is increased. IV. CONGENITAL HAEMOLYTIC ANAEMIA 1. 2. 3. 4. a. Hb is reduced. PBS Polychromasia, basophilic stippling, Heinz bodies, macrocytes are seen. MCV and MCH is increased. Enzyme assays should be done to detect various enzyme deficiencies. G6PD deficiency 1. Brilliant cresyl blue test. 2. Heinz body test. 3. Fluorescent spot test. 4. Enzyme assay. Phosphokinase deficiency. Pyruvate kinase deficiency. Hb may be normal in acute phase. PBS Polychromasia, basophilic stippling and reticulocytes. Osmotic fragility test is increased. Direct Coomb's test may be positive. Serological test for antibodies in serum. Urine test may show increased levels of coproporphyrin. Other tests to know the cause may be done depending on the clinical features for eg. Malarial parasites in malaria.

b. c. 1. 2. 3. 4. 5. 6. 7.

V. ACQUIRED HAEMOLYTIC ANAEMIA

86

VI. PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA 1. 2. 3. 4. 5. 6. Hb is decreased to less than 5gm/dl. PBS dimorphic anaemia. Total leucocytes and platelets are reduced. Reticulocytosis is seen. Bone marrow shows erythroid hyperplasia. Urine Hb casts, haemosiderinuria is a constant feature

VII. APLASTIC ANAEMIA: 1. 2. 3. 4. 5. 6. Hb is decreased. PCV is decreased Total leucocytes count is decreased. Differential count shows marked neutropenia. Platelets are decreased. PBS usually normal cells are seen sometimes macrocytosis, anisocytosis and poikilocytosis is seen. Bone marrow is hypoplastic or aplastic, shows numerous spicules with empty fatty spaces. Dyserythropoietic lymphocytes, plasma cells and macro phages. Relatively few haemopoietic cells. Serum Iron is increased. Plasma erythropoietin is increased. Coagulation profiles are abnormal.

7. 8. 9.

Lastly, anaemia may be a feature in leukemias. Here leucocytes and reticulocytes are increased. Normochromic RBC's are seen. Bibliography: 1. 2. 3. 4. 5. 6. 7. Cecils text book of Medicine. de Gruchy's clinical haematology in medical practice. Harrison's text book of Principles of internal medicine. Text book of Haemotology basic principles and practice by Hoffman co.et al. Blood Principles to practice of Haematology by R.I. Hand , S.Lux and T.P. Russel. Text book of Medical laboratory technology by Ramnik Sood. Practical pathology Dr.U.Chaturvedi and T Singh.

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MANAGEMENT OF IRON DEFICIENCY ANEMIA IN PREGNANCY

Dr. Jyothika A. Desai Dr. P.R. Desai Hospital, Bangalore Anaemia is not a disease. It is a sign of an underlying disorder.Treatment, therefore, must be preceded by an accurate diagnosis of the cause and the type of anemia. General Measures Diet A basic knowledge of iron metabolism in the body will help us in understanding the mechanisms by which the iron supplements help in correcting the deficiency. Iron absorption Healthy people absorb around 5 to 10 percent of the iron in their daily diets. Absorption is highest in childhood, and reduces with age. Iron is present in animal foods in organic 'heme' form and in plant foods in inorganic 'nonheme' form. The heme and nonheme forms of iron are absorbed by different mechanisms. About 20 to 30 percent of heme iron is absorbed compared to only 2 to 5 percent of nonheme iron. Heme iron is broken down by pancreatic enzymes and is absorbed. Its absorption is unaffected by food factors. Non Heme iron must be in ferrous form to be absorbed and the hydrochloric acid of the stomach converts ferric iron to ferrous iron. Iron absorption is a slow process, taking between two and four hours. Iron levels in the body are regulated by absorption, rather than by excretion and low body iron levels lead to improved absorption. In cases of iron deficiency absorption efficiency increases to around 10 to 20 percent. Various food factors affect iron absorption and the overall amount of iron absorbed from a meal will depend on the interactions between these factors.
Enhancers and Inhibitors of Non heme iron absorption

Enhancers
Low body stores

Inhibitors
Full body stores

Hydrochloric acid in the stomach Reduction in stomach acid Vitamin C Sugars Haem iron Tannins (e.g. in tea) Oxalic acid (e.g. in spinach) Phytic acid (in dietary fibre) Calcium and phosphorus in milk

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Food Fortification is a preventive measure that aims at improving and sustaining iron nutrition on a permanent basis.Cereals, sauce, sugar, curry powder and salt are some of the items which are fortified with iron. Treatment of Hookworm infestation a) b) c) a) Albendazole 400mgs | only in the 2nd or 3rd trimesters Mebendazole100 mgs twice daily for 3 days | only in the 2nd or 3rd trimesters Avoiding walking barefoot to prevent Hookworm infestation To raise the Hb level

Aims of Therapy b) To replenish the iron stores Choice of Therapy depends upon a) c) Severity of Anaemia Associated complicating factors b) Duration of pregnancy and Principles of iron therapy First introduced by Dr.Pierre Blaud in the 19th century. 1. 2. 3. 4. 5. Inorganic iron salts should be given orally A raise in Hb concentration of about or > 0.5 gm per 100cc daily is considered a positive response Once the Hb concentration has risen to the normal range, iron therapy should be given for a further period of 3 months to replenish the iron stores. Response to parenteral iron is almost similar to oral iron- in the absence of malabsorbtion. Bone marrow response and erythroid hyperplasia are seen within 48 hrs of starting therapy and iron stores are replenished within 3 months.

Iron Therapy can be a) oral or b) parenteral Oral iron Iron is best absorbed in the ferrous form. It is available as various salts -gluconate, fumarate,sulphate, succinate, etc. Ferrous Sulphate is available as a 200mg tablet with 60 mgs of elemental iron along with traces of zinc and magnesium. The therapy is started with 1 tablet

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thrice daily with food, followed by gradually increasing the dosage to 2 tablets thrice a day. Once the Hb has reached normal values, it can be maintained at 1 tablet a day for 3 months to replenish the iron stores. Recommended daily requirement of iron: For prophylaxis, the Govt of India recommends 100 mgs of elemental iron with 0.5 mg of Folic Acid, but for treatment, more than 180 mgs of elemental iron with 5 mgs of Folic Acid is recommended.W.H.O recommends 30-60 mgs of iron be given daily to pregnant women with normal iron stores and 120-240 mgs to those with none. Drawbacks of oral iron therapy a) Gastro-intestinal side effects seen in 10% of women. It is dose related and is less when the iron is <100 mgs per day. It depends upon the amount of ionic iron - the absorbable form of iron that comes in contact with the gastro-intestinal mucosa. The common symptoms are epigastric distress, nausea, vomiting, constipation, diarrhoea etc.They can be avoided by Starting with a small dose and gradually increasing it, By changing the preparation. Carbonyl iron and Hb preparations are better tolerated Giving it with meals. Slow release preparations, which are generally more expensive are said to be relatively free from side effects. This is perhaps so because much of the iron is not released at all or is unabsorbed and excreted unchanged.

1) 2) 3)

b) Unpredictable absorptiontherefore cannot be depended upon when a quick response is desired. Iron absorption is diminished by antacids, oxalates, phosphates in bread, milk and cereals, and tannins in tea. Iron absorption is increased byascorbic acid, lactate, aminoacids, sugar, citric acid, HCL in the stomach, meat etc. Response to therapy is evidenced by a) Rise in Hb levelA rise in 0.1gm% or more daily is considered a positive response. Hb response is greater in the first few weeks of therapy and is proportional to the severity of anaemia.A rise in Hb concentration of 1gm% per wk in the non-pregnant state or 0.8gm%per wk in pregnancy can be expected with adequate iron treatment whether oral or parenteral. Reticulocytosis within 7-10 days If no significant improvement is evident clinically and haematologically within 3 wks of therapy, the diagnosis should be reviewed. Causes of failure of improvement a) Noncompliant patient who does not take the prescribed dosage b) Defective absorption either because of the preparation or because of coexisting gastrointestinal disorders
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b) Haematocrit comes to normal c) d) Subjective symptoms increased sense of well-being, improved appetite,etc

c) d) e) f) a)

Incorrect diagnosis of the type of anaemia Concurrent blood loss due to hookworm infestation or bleeding piles Coexistent undiagnosed folate deficiency Inhibition of erythropoiesis due to infection Intolerance to oral iron

Contraindications to Oral iron therapy b) Severe anaemia in advanced pregnancy Indications for Parenteral iron therapy a) c) d) a) b) a) Intolerance to oral therapy Severe anaemia in advanced pregnancy Malabsorbtion syndrome Certainty of iron administration Replenishment of iron stores Intramuscular b) Non compliant patient

Advantages of Parenteral therapy

Routes of administration b) Intravenous Calculation of total iron deficit: Total iron deficit in adult patients may be estimated using one of the following equations (Hbt = target Hb level; Hbo = observed or actual Hb level; Bwt = body weight) Total Dose (mg) = 50 {0.0442 Bwt (Hbt - Hbo) + (0.26 Bwt) } Total Dose (mg) = 2.4 Bwt (15 - Hbo) + 500 Contraindications and Precautions: v Parenteral iron supplementation is ineffective in aplastic or hypoplastic anemia and acute leukemia. v Parenteral iron supplementation is contraindicated in early pregnancy, in patients with liver disease or acute renal failure. v IV iron products must be used with caution to minimize acute adverse reactions. An anaphylaxis management kit should be at hand. v Conservative estimates of iron deficit should be used to avoid iron overload. v Measures of iron status (ferritin, total iron binding capacity, & transferrin saturation) and red blood cell indices must be checked periodically to reevaluate the patient's need for additional iron supplementation. Parenteral iron should not be administered to patients with ferritin >
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800 ng/mL or transferrin saturation > 50%. Intramuscular iron Preparations available are Iron-Dextran (Imferon), (Ferri) Iron Sorbitol Citric Acid Complex (Jectofer) All preparations contain 50 mgs of elemental iron in 1 cc. Oral iron should be suspended 24 hrs before starting parenteral iron. The dose of Intramuscular iron calculated as per the formula which is the same as for Intravenous iron. The total dose of Iron Sorbitol CAC is adjusted because 30% is excreted in the urine. Test dose of 1cc is given followed by daily or alternate day IM injections in doses of 2cc. Drawbacks Local - pain, pigmentation, abscess formation. Few precautions taken while injecting can prevent these local reactions like utilizing the Z technique, injecting air or saline before withdrawing the needle and not massaging the injection site. Systemic a) c) Diarrhoea, nausea, vomiting, fever, lymphadenopathy Arthralgia, especially in rheumatoid arthritis. b) Anaphylactic reaction in 2 % of patients d) Haemolysis Intravenous iron The various preparations available are Iron Dextran (Imferon, Ferri), Iron Hydroxide Sucrose Complex (Encifer) etc.Intravenous iron can be given as a single or multiple dose without dilution or diluted as a total dose infusion. A test dose of 0.5 cc diluted with 4-5 cc of the patient's blood is injected slowly and patient observed for 1 hour. If there is no reaction, upto 5 cc can be given slowly as a single bolus at the rate of 1cc/minute. Total dose infusion The total dose calculated is diluted in 1 litre of saline or dextrose. Saline is preferred as phlebitis is less often seen. Not more than 2500mgs can be given in 1 litre.If the total dose is more than 2500mgs or 50 cc (1cc=50mg), then the total dose should be infused on 2 consecutive days. The formulae for calculating the total dose are as follows a) b) c) 2.3 x wt in kgs x (15pt's Hb% in gms) +1000mgs(for stores) 0.3 x wt in lbs x (100Hb %) + 50% for stores A simple method is to give 250 mgs of elemental iron for each gm of Hb below the normal (14 gms) and add 50 % more for replenishment of iron stores.

Technique for Total dose infusion Precautions as for a blood transfusion should be taken. The drip rate should be about 10 drops/minute for the first 20 minutes. It can be later increased to 40 drops/minute. Any reaction
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like rigors, chest pain etc, calls for immediate suspension of the drip. Iron Hydroxide Sucrose Complex is not licensed for total dose infusion and can be given as 5cc (vial contains 5cc with 20mg/cc) slow IV or as a short infusion for 15 minutes with N.S for 1-3 doses per week. It has excellent tolerance with few complications. Advantages of Total dose infusion a) c) It eliminates repeated and painful IM injections Expenditure is less than for the IM course b) The treatment is completed in 1 day Blood transfusion in pregnancy Considered only in severe anemia close to delivery where packed cells transfusion is given. The other major indication for blood transfusion in pregnancy is in management of acute blood loss as in APH /PPH Antenatal management of a case with anaemia The prognosis is good if anaemia is detected and treated in time. Therapeutic dose of oral iron should be started after the 14th week. The patient should be seen more often to detect and manage the complications of anaemia such as Heart failure, Preterm labour etc. Fetal growth to be monitored carefully as IUGR is commonly seen. Betamimetics should be given with caution in patients with anaemia and preterm labour to avoid the risk of pulmonary oedema. Management during labour The aim is to have a normal delivery. Ideally, anaemia should have been treated during pregnancy but in the event of a patient arriving in labour with untreated anaemia then in the First stage a) b) c) e) The patient should have back rest or should be in any other comfortable position Pain relief should be offered O2 inhalation if patient is breathless. This will also reduce the risk of fetal hypoxia. Digitalisation if in failure with severe anaemia

d) Prophylactic antibiotics may be required. Second stage Should be shortened by Outlet forceps /vacuum. Prophylactic oxytocics should be given to curtail blood loss. Third stage Should be managed actively. Significant blood loss should be replaced with fresh packed cells. Puerperium The problems faced are:

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v Subinvolution of the uterus due to infection v Poor lactation v Thromboembolism Oral iron should be given for at least 6 months. Contraception Spacing of pregnancies is very important for an anaemic woman. Progesterone only preparations are preferred. In a non lactating woman COCs are a good alternative since blood loss during menstruation is minimal. IUCD may be considered if there is no history of menorrhagia. To reiterate, an anaemic woman must use an effective method of contraception and avoid pregnancy for at least 2 yrs to give time for her iron stores to be replenished. Bibliography 1. 2. Scott DE, Pritchard JA: Iron deficiency in healthy young college women. JAMA 1967; 199:897-900. Roszkowski I, Wojcick J, Zaleska K:Serum iron deficiency during the third trimester of pregnancy: Maternal complications and fate of the neonate. Obstet Gynecol 1996; 28:820825. Thompson WB: Comparison of tests for diagnosis of iron depletion in Pregnancy. Am J Obstet Gynecol 1988; 159:1132-1134. Goepel E, Ulmer HU, Neth RD: Premature labour contractions and the value of serum ferritin during pregnancy. Gynecol Obstet Invest 1988; 26:265-273. Stein ML, Gunston KD, May RM: Iron dextran in the treatment of iron deficiency anemia of pregnancy: Haematological response and incidence of side effects. S Afr Med J 1991; 79:195196. Taylor DJ, Mallen C, Mc Dougall N, Lind T. Effect of iron supplements on serum ferritin levels during and after pregnancy. Br J Obstet Gynaecol 1982; 89:1011-17. World Health Organisation. Nutritional Anaemias. WHO, Geneva, 1972. De Leeuw NK, Lowenstein L, Hsieh YS. Iron deficiency and hydremia in normal pregnancy. Medicine (Baltimore) 1966; 45:291-315. World Health Organisation. Prevention and management of severe anemia in pregnancy. Report of a Technical Working Group, Geneva, 20-22 May 1991. Maternal Health and safe Motherhood Programme. WHO, Geneva, 1993.

3. 4. 5.

6. 7. 8. 9.

10. Chisholm J. A Controlled clinical trial of prophylactic folic acid and iron in deficiency. J Obstet Gynaecol 1966; 73:191-6. 11. Rios E, Lipschitz DA, Cook JD Smith NJ. Relationship of maternal and infant iron stores as

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assessed by determination of plasma ferritin. Pediatrics 1975; 55:694-9. 12. Halleberg I, Ryttinger L, Solvell L. Side effects if oral iron therapy. Acta Med Scand 1966; 459 (Suppl):3-10. 13. Stein ML, Gunston KD, May RM. Iron dextran in the treatment of iron Deficiency anaemia of pregnancy. Haematological response and incidence of side effects. S Afr Med J 1991; 79:195-6. 14. AI-Momen AK, Al-Meshari A et al. Intravenous iron sucrose complex in the treatment of iron deficiency anaemia during pregnancy. Eur J Obstet Gynecol Reprod Biol 1996; 69; 121-4. 15. Anonymous. Do all pregnant women need iron? Br Med J 1978; ii: 1317. 16. Schwartz WJ, Thurnau GR. Iron deficiency anaemia in pregnancy. Clin Obstet Gynecol 1995; 38:443-454. 17. Turmen T, Abou Zahr C. Safe motherhood. Int J Gynecol Obstet 1994; 46:145-153. 18. Sharma JB, Medical complications in pregnancy. In:Sharma JB. (ed) The Obstetric Protocol, 1st edn. Delhi: Jaypee Brothers, 1998; 78-98. 19. Letsky E. Blood Volume, haematinics, anaemia. In: de Swiet M. (ed) Medical Disorders in Obstetric Practice, 3rd edn. Oxford Blackwell, 1995; 33-60. 20. World Health Organisation. Report of a WHO Group of Experts on Nutritional Anaemias. Technical report series no. 503, Geneva: WHO, 1972. 21. Abel R, Rajaratnam J, Sampathkumar V. Anaemia in pregnancy. Impact of iron, Deworming and IEC, RUSHA Dept. Tamil Nadu: CMC Vellore, 1999. 22. Indian Council of Medical Research. Evaluation of the National Nutritional Anemia Prophylaxis Programme. Task Force Study. New Delhi: ICMR, 1989. 23. Hulten LE, Gramatkovski A, Gleerup A, Hallberg L. Iron absorption from the whole diet. Relation to meal composition, iron requirements and iron stores. Eur J Clin Nutr 1995; 49: 794-808. 24. Hallberg L, Bjorn Rassmussen E. Determination of iron absorption from whole diet. A new tool model using two radiation isotopes given as haem and non-haem iron. Scand J Haematol 1972; 9:193-197. 25. Stolzfus R, Dreyfuss ML, Guidelines for the use of iron supplements to prevent and treat iron deficiency anaemia. Geneva: INACG, WHO, UNICEF, 1998. 26. Sharma JB, Arora BS, Kumar S, Goel S, Dhamija A. Helminth and protozoan intestinal infections: an important cause for anemia in pregnant women in Delhi, India. J Obstet Gynecol Ind 2001:51(6):58-61. 27. Sloan NL, Jordan EA, Winikoff B. Does Iron supplementation make a Difference? Mother
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Care Project, 15 Arlington, VA, USA. 1992. 28. Milman N, Bergholt T, Byg KE Eriksen L, Graudal N. Iron status and iron balance during pregnancy. A critical re-appraisal of iron supplementation. Acta Obstet Gynecol Scand 1999; 78:749-757. 29. Sharma JB. Iron deficiency anaemia in pregnancy-still a major cause of maternal mortaility and morbidity in India. Obs Gynae Today 1999: IV: 693-701. 30. Rusia UN, Madan N Agarwal N, Sikka M, Sood SK. Effect of maternal iron deficiency anaemia on fetal outcome. Ind j Pathol Microbiol 1995; 38:273-279. 31. Mahomed K. Routine iron supplementation during pregnancy. (Cochrane Review) The Cochrane Library, Issue 2. Oxford; Update Software 1998. 32. Ridwan E, Schlultink W, Dillon D, Gross R. Effects of weekly iron supplementation on pregnant Indonesian women are similar to those of daily supplementation. Am J Clin Nutr 1996; 63:884-890. 33. Bhatt RV. Poor iron compliance the way out. J Obstet Gynecol Ind 1997; 47:185- 190. 34. Atukorala T, deSilvla LD, Dechering WH, Dassenaeike TS, Perera RS. Evaluation of effectiveness of iron folate supplementation and antihelminthic therapy against anaemia in pregnancy- study in the plantation sector of Sri Lanka. Am J Clin 1994; 60:286-292. 35. Bhatt RV. Anaemias in pregnancy: early diagnosis and treatment. J.Ind Med Assoc 1995; 93:80-82. 36. Indian Council of Medical Research. Field Supplementation Trial in Pregnant Women with 60 mg, 120 mg and 180 mg of Iron with 500 ugm., of Folic Acid . New Delhi: ICMR, 1992 37. Sood SK, Madan N, Rusia U, Sharma S. Nutritional anaemia in pregnancy and its health implications with special reference to India. Ann Nati Acad Med Sci 1989; 25:41-50 38. Prema K. Anaemia in pregnancy. In:Ratnam SS, Rao KB, Arulkumaran S. (eds) Obstetrics and Gynaecology,. Vol. I Madras: Orient Longman,1992; 42-53. 39. Basu SK. Administration of iron dextran complex by continuous intravenous infusion. J Obstet Gynaecol Br Cwlth 1965; 72:253-258 40. Blot I, Papiemik E, Kaltwasser JP, Werner E, Techernia G. Influence of routine administration of folic acid and iron during pregnancy. Gynecol Obstet Invest 1981; 12:294304. 41. Swalin RA, St. Clair L. The role of folic acid in deficiency status and prevention of disease. J Fam Pract 1997; 44:138-144. 42. Chanarin L. Folate deficiency in pregnancy. In: Chanarin I (ed). The Anaemias, 3rd edn. Oxford: Blackwell, 1990:140-148 Megaloblastic

43. Iyengar L. Folic acid requirements of Indian pregnant women. Am J Obstet Gynecol 1971; 111: 13-16.
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Eating right, right from now!

Dr. Sita Bhateja Sita Bhateja's Nursing Home, Bangalore

Anemia is the commonest cause of poor health amongst Indian women. There are so many causes of this malady but we shall talk only about the nutritional anemia. About 60% of the women have hemoglobin less than 10 gms/dl. They are not always from the lower socio-economic class. This is also prevalent amongst the middle and high socio-economic strata of women in our country. This is basically due to poor knowledge about nutrition. Causes of poor nutrition 1. 2. 3. Lack of information regarding balanced diet, specifically the anti-anemic factors. Stereotype of menu same quality of food day after day. Eating wrong type of food, what is more commonly known as junk food! Foods which are uncooked, cold aerated drinks, white flour preparations, and sweet, sugar coated food items like chocolates are the types of food which have poor nutritional value. These food items kill appetite and are habit-forming. In case of pregnant women and adolescents the requirement is much more. This must be taken into account by the individuals while they are preparing their food and they must be educated about their diet by the treating doctors. If there is heavy blood loss due to heavy menstrual cycle, bleeding piles or any other cause for chronic blood loss, it will cause anemia.

4.

5.

In early months of pregnancy women develop anemia due to vomiting which causes loss of nutritional products from the diet. There should be a balanced diet. Many of these dietary factors are inter-dependent for absorption. Variety of food is the key to getting all the ingredients which would prevent nutritional anemia. Chronic deficiency of hemoglobin leads to poor vitality and fatigue. Essential ingredients for preventing anemia are: Iron Folic acid Vitamin B12 Vitamin C Trace elements Zinc, Chromium, Selenium. The chart shows what is the requirement and in which food they are to be found.

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The modern educated woman is aware of the problems. Nowadays some of them come for preconception checkup. That is the best time to diagnose pre-existing anemia and cure it well before the pregnancy. This will ensure proper oxygen supply to the fetus from the very beginning. Chronic oxygen deficiency due to maternal anemia will produce poor pregnancy outcome. The modern diet is very deficient in folic acid because it is destroyed by cooking. Therefore some fresh green raw vegetables will be desirable. Eg. Lettuce, sprouted beans. In addition folic acid supplement is very necessary. Vitamin B12 is an ingredient which is found mostly in nonvegetarian diet. Lot of people in India are vegetarians. It is necessary to supplement the diet with B12 tablets. Vitamin C is another unstable ingredient. It promotes iron absorption. Citrus fruits and amla are good sources. Unpeeled potatoes are a good source of vitamin C. Other trace elements may not be easily available in diet. Therefore the simplest solution is to supplement these with tablet or injections. Calories may be sufficient in the diet but due to lack of information or due to poor eating habits anemia is still very prevalent. 60% of female population has hemoglobin of 10grms or even less. Hemoglobin of more that 11grms is very uncommon. This makes them vulnerable to complications. Even very small blood loss during delivery may cause symptoms of hemorrhage in these cases. It is necessary to repeatedly check hemoglobin levels and attend to the nutrition supplements. This cause of maternal mortality and morbidity can be easily prevented by proper nutrition and supplementation. It is not possible to procure all anti-anemic factors in the diet. In view of this supplementation is the best way to fight this scourge which leads to poor vitality. Our aim is to have every woman with hemoglobin of at least 12gms. This will help in reducing mortality and morbidity of the mothers and open the doors to happiness in the family. She can then have energy to look after her family and also to produce enough milk for her new born baby. Let us make the Indian women enjoy her role to the full.

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Ideal Body Weight and Recommended Caloric Intake During Pregnancy

Height 4'10 4'11 5'0 5'1 5'2 5'3 5'4 5'5 5'6 5'7 5'8 5'8 5'9 5'10 Recommended Caloric Intake Ideal Body Weight During Pregnancy ( 35 Kcal / Kg ) (Kilograms) 48.6 50.0 51.4 52.7 54.1 55.9 58.2 60.0 61.8 63.6 65.7 65.7 67.3 69.1 1701 1750 1799 1845 1894 1957 2037 2100 2163 2226 2300 2300 2356 2419

Nutrient Requirements In Women

Nutrient Normal RDA RDA during pregnancy Risks of deficiency in mother and fetus Intrauterine growth retardation, malformations, premature and postmature birth, LBW, perinatal death and abnormal delivery with dystocia and placental abruption Maternal anemia, fetal anemia, LBW and preterm delivery Sources Red meat, sea food, yogurt, bread, lentils, milk, peas, baked potatoes.

Zinc

12 mg/ day

15 mg/ day

Iron

15 mg/ day

30 mg/ day

Apple, jaggery, dry fruits

Copper

1.5 - 3 mg/ day

1.5 - 3 mg/ day

Placental insufficiency and intrauterine death

Cooking in copper vessel

Chromium

50 - 200 :g/ day 50 - 200 :g/ day

Gestational diabetes and hyperglycemia

Onions, tomatoes, broccoli, white meat, grape juice, red meat, green beans. Asparagus, mushroom, garlic, red meat, sea food.

Selenium

55 :g/ day

65 :g/ day

Neural tube defects, sudden infant death syndrome and first- trimester miscarriages Miscarriage, stillbirths, congenital anomalies., goiter, cretinism, impaired brain function and hypothyroidism

Iodine

150 :g/ day

175 :g/ day

Iodized salt, sea food

Folic acid

15 :g/ day

Neural tube defects in fetus

Meat, liver ( best source), chicken kidney, egg yolk, almonds, lentils, beetroot, banana, whole wheat grain

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Recommended Dietary Intakes For Indians (ICMR 1990)

Adult Women

Additional In Pregnancy

Food Items (Gms) Moderate Work Heavy Work Gms Kcal 410 440 575 35

Sedentary Work

Cereals

118

Pulses

40

45 50

15

52

Milk

100

150

200

100

83

100

Fat 20 25 40

Sugar 20 20 40

10

40

Leafy vegetables 100 100

50

Other vegetables 40 40

100

Roots and tubers

50

50

60

Total (Kcal / day) 1875

2225

2925

160

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Mirror, mirror on the wall. which is the best iron of them all?
Dr. Susheela Rani B. S. Manjushree Speciality Hospital Bangalore

Iron deficiency is the most common nutritional disorder in the world. The World Health Organization ranked it as the seventh most important preventable risk for disease, disability, and death in 2002. In a developing country like ours the woman is always in a state of precarious iron balance during the reproductive years. She is born anemic, grows anemic, and enters the pregnancy in an iron deficient state and becomes even more anemic with successive pregnancies. The iron stores are not well developed because of poor nutritional intake, recurrent infections, menstrual blood loss and repeated pregnancies. Gender discrimination in our country ensures that the girl child lacks access to balanced diet, adequate health care and proper education. Thus the average Indian woman is almost always in an iron deficient state. The most common strategies employed to control the iron deficient state are: 1. Food fortification 2. Iron supplementation The Recommended Dietary Allowance (RDA) for females
Category Adolescent girls Premenopausal Postmenopausal Mixed Diet 18 mg 25 mg 8 mg Veg Diet 26 mg 33 mg 14 mg

Supplementation of Iron in pregnancy 60mg /day Treatment of Iron deficiency 120 - 180mg /day Iron Toxicity Iron poisoning is rare in adults, but serious acute toxicity may occur in children. The estimated lethal dose of iron is 200 to 300 mg/kg. The majority of cases are non-fatal and without serious morbidity. Fatalities are generally attributable to accidental ingestion of adult, rather than paediatric, iron supplements. Many iron preparations are therefore aimed at making them safe by increasing the lethal dose. Iron fortification of food Food-iron fortification (at levels to provide around 515 mg/day, in foods such as wheat flour, salt, sugar, rice, fish sauces and pastes) is common in developing countries, where iron
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deficiency is widespread and food fortification is relatively inexpensive in comparison to pharmacological supplementation. In the UK there is mandatory iron fortification of white and brown flour. Many breakfast cereals, malted drinks, some biscuits and snack foods are fortified on a voluntary basis. Ferrous sulfate is the most commonly used fortificant for cow milk or infant formulas. Rice fortified with a standard ferrous sulfate mix has been used successfully in the Philippines. Curry powder has been successfully fortified with iron- EDTA in South Africa. The technology for fortifying common salt with iron has been developed A factory where wheat flour is indigenously in India.
fortified with iron

A double-blind controlled iron fortification trial using NaFeEDTA in masala powder (10 mg/g masala) was directed towards an iron deficient Indian population. The iron status of the fortified groups improved more than that of control subjects, the prevalence of iron deficiency anaemia decreased from 22 to 5% in fortified females. It is reported that fortified subjects with normal iron status did not accumulate excessive body iron and no adverse effects were observed.

Another double blind randomized controlled study was conducted among school children in Bangalore, India. The study showed that when school children were fed with extruded rice fortified with micronized ground ferric pyrophosphate in their midday meal for 7 months, iron deficiency anemia was reduced by 50%. Thus it has been proven beyond doubt that iron fortification of food can make a positive difference to the health statistics of our country.

Pharmacological iron supplementation

A wide range of iron containing products (more than 70) is available in pharmacies. These include products that contain only iron salts, iron combined with zinc and/or folic acid and numerous multinutrient products. The indication for products that only contain iron is the treatment or prevention of iron deficiency. The multinutrient products have a range of indications including use when intake or absorption of nutrients may be suboptimal such as postoperatively, in severe chronic disease, in malabsorption syndrome, in pregnancy and where diet is restricted.

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Side effects of Iron supplementation Therapeutic doses of iron supplements, which are prescribed for iron deficiency anemia, may cause gastrointestinal side effects such as nausea, vomiting, constipation, diarrhea, dark colored stools, and/or abdominal distress. Enteric coating & delayed release Modified release [MR] preparations, some in 'Spansule' formulation, are designed to release iron gradually as the preparation traverses the GI tract so that at any given time, only a small amount of iron is present in the lumen. The advantages claimed are less GI irritation and a long duration of action permitting once or twice daily dosage. However, these preparations are likely to carry the iron beyond the first part of the duodenum where the conditions for iron absorption are optimal and the lower incidence of intolerance may well be due to the fact that a smaller quantity of iron is actually released and absorbed. Furthermore, technical failure of the preparation can lead to dose-dumping and even to entire tablets being passed out in stool. Iron absorption enhancers A variety of substances designed to enhance the absorption of iron has been marketed, including surface acting agents, carbohydrates, inorganic salts, aminoacids and vitamins. One of the more popular of these is ascorbic acid. When present in an amount of 200mg or more, ascorbic acid increases the absorption of medicinal iron by at least 30%. However the increased uptake is associated with a significant increase in the incidence of side effects; therefore addition of ascorbic acid seems to have little advantage over increasing the amount of iron administered. It is inadvisable to use preparations that contain other compounds with therapeutic actions of their own, such as Vit B12, folate, cobalt etc, since the patient's response to the combination cannot be easily interpreted. Tips to enhance iron absorption 1. 2. 3. 4. 5. Starting with half the recommended dose and gradually increasing to the full dose will help minimize the side effects. Taking the supplement with food also may help limit gastric symptoms at the cost of reduced absorption. Inclusion in the meal fresh fruits or fruit juices and other sources of vitamin C such as tomatoes, spinach, cabbage, cauliflower, potatoes and other green leafy vegetables. Consume milk, cheese and other dairy products as between-meal snacks rather than at mealtimes Separate tea drinking from mealtime by at least 2 hours

A number of iron preparations are currently available in the Indian market for the prevention and treatment of iron deficiency anemia. Each preparation claims some benefit over the others leaving

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the physician in considerable confusion. How does one choose the best iron supplement? Apart from being bio available, clinically effective and having minimal side effects, an ideal iron supplement needs to be safe and cost effective. While the effectiveness of most iron preparations available in the market remain the same, the benefits claimed are in reducing the side effects, making them tolerable and increasing their safety. Oral Iron Supplements 1. Ferrous salts All dietary iron has to be reduced to ferrous form to enter the mucosal cells. Hence bivalent iron salts like ferrous sulfate, fumarate, gluconate, succinate, glutamate and lactate have been preferred over ferric salt preparations. In addition these salts are amongst the cheapest preparations of iron available for medicinal use.
Salt of Iron Ferrous sulphate Ferrous gluconate Ferrous lactate Ferrous fumarate Irex 12 - Micro Autrin - Wyeth Softeron - Aristo Rediplex - Pfizer Livogen Z - Merck Hematrine Novartis Pharma Ferium XT - Emcure Orofer XT - Emcure Trade name - Pharma Iberol - Upjohn JP Tone - Jagsonpal

Ferrous succinate Ferrous ascorbate

Bioavailability These salts have uniformly good bioavailability. However, the bioavailability decreases markedly in the presence of dietary inhibitors like phytates, tannic acid etc. They cannot be added to other foods/milk/fortified formulas for the same reason. Clinical efficacy Despite being efficacious and cheap with good bioavailability, ferrous salts have several disadvantages particularly the high incidence of gastrointestinal side effects (~23 %). Teeth are known to be stained with liquid preparations. Ferrous sulphate has a salty astringent taste. Safety issues Any over dosage of the salt can easily override the 'mucosal barrier' to cause acute iron toxicity. The LD50 for ferrous sulphate is 320mg/Kg body weight.
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2. Ferric salts Ferric salts have traditionally not been preferred over ferrous salts as the ferric ion first requires reduction to ferrous form in the intestinal lumen and usually this reducing capacity is not enough to reduce doses of iron therapeutically administered. Bioavailablility The bio-availability of iron from ferric salts is 3 to 4 times less than that of ferrous sulphate. Therefore, the dose of ferric salts needs to be 4 times more than ferrous salts to achieve similar therapeutic effect. Safety Ferric salts carry the inherent advantage of a poor poisoning potential given the limited reducing ability of the gastric contents. Ferric ammonium citrate (18% elemental iron) is the most commonly used of these salts. 3. Iron Amino-acid chelates Iron amino-acid chelates are conjugates of the ferrous or ferric iron with amino-acids. Although numerous conjugates have been formulated the most studied of these are ferrous bis-glycinate (20% elemental iron content), ferric trisglycinate and ferrous glycine sulphate. They have no effect on the color or taste of food products. Bioavailability Their main advantage lies in their relatively high bioavailability in the presence of dietary inhibitors. It is theorized that the chelates prevent iron from binding to inhibitors in food or precipitating as insoluble ferric hydroxide in the pH of the small intestine. Studies have shown that iron absorption from ferrous bisglycinate is better than ferous sulphate in the presence of dietary phytates. Safety These conjugates have low pro-oxidant properties thereby limiting free radical damage and are environmentally stable.

Trade name Ferrous bisglycinate Fe Glycine sulphate

Pharma Ferose - CFL Hemfer - Am. Rem

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4. Iron (III) Polymaltose Complex (IPC) IPC is a novel iron preparation, which contains non-ionic iron and polymaltose in a stable complex. Bioavailability IPC and FS have been demonstrated to have equivalent bioavailability. Absorption of IPC is not affected by food or milk, enabling administration without consideration of the timing of feed. Also, to date there are no reports of any interactions with foods or medicines. Clinical efficacy The usefulness of IPC in the treatment of IDA has recently been a topic of much debate. Contrary to earlier reports, there are several other reports of inadequate or slower rise in hemoglobin. Safety Iron of IPC is absorbed in the intestine through a self-limiting competitive interchange of ligands, so that the intestinal transport system is saturated in case of over dosage. Accidental intoxication with IPC is therefore rarely seen.
Trade name Mumfer Z Pharma Glenmark

5. Carbonyl Iron Carbonyl iron is a small particle preparation of highly purified (98%) metallic iron. 'Carbonyl' describes the process of manufacture of the iron particles (from iron pentacarbonyl gas). The particle size is less than 5 microns as compared to Ferrous fumarate which is 30-100microns. The stomach acid solubilizes this iron. In the process of this solubilization H+ ions are consumed thereby increasing the gastric pH. Also, as a result the absorption of iron is slow (permitting continued release for 1 to 2 days) and self limited by the rate of acid secretion by the stomach mucosa. Bioavailability After oral administration of equivalent amounts of carbonyl and ferrous iron, the amount of iron absorbed, and the internal distribution of absorbed iron are all similar. As a food fortificant its advantages include lack of change in color or taste of the foodstuff and environmental stability. Clinical efficacy Carbonyl iron is as effective as Ferrous sulphate in bringing about mean Hb increase. Estimates of net changes in total body iron suggested that the overall bioavailability of carbonyl iron was high, about 70% that of ferrous sulfate. Subsequent studies have shown that Carbonyl iron was as effective and safe in prevention and treatment of iron deficiency with lesser side effects compared to FS.

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Safety Carbonyl iron is much less toxic than ionized forms of iron. Whereas the lethal dose of FS is 320 mg/kg. Toxicity studies of carbonyl iron in animals demonstrated a lethal dose of 50,000 to 60,000 mg/kg Trade name
Pharma Fefol Z Carboflot Richar Ferox Caf Kit GSK Glenmark Dabur Micronova Aristo

6. Iron EDTA Ethylene diamine tetraacetic acid (EDTA) is a hexadentate chelator, which can combine with virtually every metal in the periodic table. Binding of EDTA with iron is favoured in the acid milieu of the stomach, irrespective of whether the EDTA is administered as CaNa2EDTA, Na2EDTA, or NaFeEDTA, but in the more alkaline medium of the duodenum the iron is exchanged, in part, with other metals. The iron released from EDTA is absorbed by the normal physiological mechanisms. When NaFeEDTA is present in a meal, the iron moiety exchanges with the intrinsic food iron and the EDTA partially protects the iron in this common non-heme iron pool from the effects of inhibitors of iron absorption, such as phytates and polyphenols. Efficacy When iron is added as NaFeEDTA to an inhibitory meal, it is two to three times better absorbed than is iron added as ferrous sulfate. Safety There is no evidence that NaFeEDTA in the dose range proposed for food fortificants (5 to 10 mg iron daily) will have any direct toxic effects. Na2EDTA and CaNa2EDTA have proved safe over a number of years, while the Joint FAO/WHO Expert Committee on Food Additives concluded in 1999 that NaFeEDTA "could be considered safe when used in supervised fortification programs" NaFeEDTA seems to be an appropriate fortificant for developing countries; its cost is about six to eight times that of ferrous sulfate in terms of equivalent amounts of iron. Its better absorption (a factor of 2-3) might make it possible to halve the daily fortification level but, it still remains expensive and there is a pressing need for food grade NaFeEDTA at more affordable prices.
Trade name Redfine Nobefer plus Haemgrow Pharma Dr. Reddy's Lab Ochoa Fem Care
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7. Other iron formulations Several other iron preparations are in various stages of development or being gradually phased out. Heme based preparations. Hemoglobin as a source of iron was promoted on the basis of the high bioavailability of heme iron. However the iron content of hemoglobin is 0.34 %. As a result 300 mg of hemoglobin is required to deliver 1 mg of elemental iron which leads to large volumes and prohibitory costs. Newer preparations Ones under study include ferrous oxalate, microencapsulated ferrous sulphate and microencapsulated ferrous fumarate. Ferrous oxalate has been recently found to have good efficacy and low toxicity in studies conducted on piglets. Sprinkles Recently, a supplement containing microencapsulated ferrous fumarate (plus ascorbic acid) has been developed which can be sprinkled on any complementary food at the table given by the caregiver. Sprinkles are sachets (like small packets of sugar) containing a blend of micronutrients in powder form, which are easily sprinkled onto foods prepared in the home. Any homemade food can be instantly fortified by adding Sprinkles. Iron being encapsulated does not change the taste, colour or texture of the food to which Sprinkles are added. Similarly, a ferrous sulphate preparation microencapsulated with phospholipids was found to have equivalent bioavailability to FeSO4. These may have important implications for community intervention programmes in which initial high-dose treatment is needed because of a high prevalence of anaemia. Conclusion v In a country like India, where iron deficiency is rampant, fortification of food with iron when introduced on a large scale will make a great impact in the health of our women. v Ferrous sulfate remains the standard first-line treatment of iron-deficiency anemia given its general tolerability, effectiveness, and low-cost but with the possible risk of iron toxicity. v Carbonyl iron, iron chelates, NaFeEDTA are as good as Ferrous sulphate in terms of haemoglobin rise but are more biovailable and / or better tolerated. All these preparations are much safer than Ferrous sulphate in terms of toxicity.

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Bibilography Joydev Mukherjee Iron deficiency anemia in pregnancy, Rational Drug Bulletin, Vol12, No1, JanMar 2002 Stoltzfus R., Dreyfus M.L.. Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia. Edited by INACG, WHO and UNICEF. IUNACG. Washington.1998 Food Fortification Approaches, IH552 Elimination of Micronutrient Malnutrition Expert group on Vitamins and Minerals EVM/00/12.REVISEDAUG2002 Rebecca J. Stoltzfus, Michele L. Dreyfuss Guidelines for the Use of Iron Supplements to Prevent and Treat IDA, Int Nutritional Anemia Consultative Group Peter Jacobs, Lucille wood, Better tolerance of IPC compared with Ferrous sulphate in the treatment of Anaemia, Hematology 2000, Vol: 5, p77-83 Morgan EH, Oates PS. Mechanisms and regulation of intestinal iron absorption Blood Cells Mol Dis. 2002 Nov-Dec;29(3):384-99 Devasthali SD, Gordeuk VR, Bioavailability of carbonyl iron: a randomized, double-blind study. 2: Eur J Haematol. 1991 May;46(5):272-8. Gordeuk VR, Brittenham GM, High-dose carbonyl iron for iron deficiency anemia: a randomized double-blind trial. Am J Clin Nutr. 1987 Dec;46(6):1029-34. Anna EO Fisher, Declan P Naughton Iron supplements: the quick fix with long-term consequences Nutriton Journal, Jan 2004, Vol 32, p 1-5 Christofides A, Asante KP, Multi-micronutrient Sprinkles including a low dose of iron provided as microencapsulated ferrous fumarate improves haematologic indices in anaemic childre. Matern Child Nutr. 2006 Jul;2(3):169-80 Zimmermann MB, Muthayya S, Moretti D, et al. Iron fortification reduces blood lead levels in children in Bangalore, India. Pediatrics. 2006 Jun;117(6):2014-21.

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REFRACTORY ANEMIAS IN PREGNANCY

Dr. Biliangady Reeta H. DNB, DGO Director: 'NORTH STAR' Hospital for Women Bangalore Definition: Refractory anemia is anemia which does not respond to therapy or shows incomplete response to adequate doses of hematinics. CASE - DISCUSSION Mrs. G aged 22 years seen at fifteen weeks gestation with Hb of 7.3g% PCV of 23% is started on seen at 15 weeks gestation is started on iron supplement containing 60mg of elemental iron in a dose of two tablets per day four weeks later a repeat Hb test shows Hb to be 7.5g% and a PVC of 24%. A peripheral smear at this time is reported as one of Microcytic Hypochromic type. The iron preparation is changed from one of ferrous gluconate to ferrous fumarate and Hb is repeated after four more weeks. The report is given as 8.0g%. This is a common situation encountered in clinical practice. Normal expected response to iron therapy: Hematological response to iron therapy in the form of increased Hb varies with the degree of anemia. When anemia is exclusively due to iron deficiency Hb takes usually two months to reach normal values. However when there is no cause for anemia other than iron deficiency the Hb should increase to a point half way between the starting level and the normal in about eighteen days . If this does not happen one should find out the cause for refractoriness to therapy. Causes of refractoriness to therapy: i. ii. Wrong diagnosis Non Compliance.
1

iii. Persistent cause for anemia. Wrong Diagnosis: Failure of response to treatment is often due to wrong clinical diagnosis of the cause of anemia or wrong diagnosis of the type of anemia. The commonest type of anemia encountered in pregnancy is iron deficiency anemia.. Megaloblastic anemia however is seen in only 3 4% of women with anemia during pregnancy and in the vast majority it is due to Folic acid deficiency Vitamin B12 deficiency begins often in the third trimester or after delivery and is mainly due to dietary deficiency which commoner amongst vegetarians. Clinical manifestations develop when the tissue stores are completely exhausted. Addisonian Pernicious anemia is rare in the reproductive years. Also severe Vitamin B12 deficiency is associated with infertility. Chronic tropical sprue is another rare cause of Vitamin B12 deficiency in pregnancy when anemia is refractory to iron therapy Folate and

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Vitamin B12 deficiency is to be suspected and investigations must be directed accordingly. The essential feature of iron deficiency anemia is diminished concentration of hemoglobin in microcytic red cells where as the red cell number need not be reduced. The Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin (MCH) are reduced. The first indication of megaloblastic anemia, irrespective of whether it is Folate or Vitamin B12 deficiency in pregnancy is an elevated MCV. A reticulocyte count count however might help to differentiate Folate from B12 deficeincy the count is normal in Vitamin B12 and elevated in Folate deficiencies. Also in case of iron deficiency anemia which is not accompanied by folate deficiency hypesegmentation of polymorphonuclear leucocytes is the characteristic feature. This is absent in associated folate deficiency. Hence diagnosis of folate deficiency in pregnancy is on morphologic grounds and is best done by examining a smear of bone marrow aspirate. (For details refer to chapter 'Investigations; What, When & Why') Management of Folate Deficiency in Pregnancy: WHO recommends a daily dose of 400g of Folate during pregnancy and postpartum. Since the diet of majority of pregnant women does not provide this requirement it is recommended to supplement pregnant women with 0.4mg per day of Folic acid Once megaloblastic erythropoiesis is established it is an indication that there is megaloblastic change in the gastrointestinal tract also. This is associated with malabsorption and treatment becomes difficult. However as a first line of treatment oral folic acid in a dose of 5.0mg per day is recommended. In case of persisting anemia parenteral folic acid may have to be tried. The recommended dose is 1 mg per day for one week . The recommended intake of Vitamin B12 is 3g per day during pregnancy which is available in the diet of a non - vegetarian. However a strict vegetarian needs to be supplemented. In case of established Vitamin B12 deficiency parenteral Cyanocobalamin should be administered in a dose of 250g per month. In women close to delivery cyanocobalamin in the dose of 100g per day for a week may be necessary . Hemoglobinopathies: Hypochromic anemia in pregnancy is mainly due to iron deficiency. However if the anemia does not improve in spite of adequate iron and folate supplements it is necessary to rule out the less common situations where the red cell morphology is abnormal not due to lack of iron but is due to lack of iron utilization or due to abnormal globin synthesis in the red cell precursor. Hemolytic anemias which could be either acquired immune hemolytic type or hemolytic anemias associated with hemoglobinopathies e.g. sickle cell trait, beta thalassemia minor and sickle cell disease (For details refer to relevant chapters). Noncompliance as a cause of refractory anemia: It is common among pregnant women in our country to either take iron irregularly or discontinue therapy often because of gastrointestinal side effects. A detailed questioning is necessary. Often one may have to obtain the details from the spouse or a caretaker at home. Iron intolerance in the form of nausea, vomiting, abdominal discomfort, colicky pain, diarrhea or constipation with conventional therapeutic dose is common
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3 3 2

in pregnancy. Symptoms are often dose related. These can be avoided by starting smaller doses of iron which can be increased gradually and also by administering iron with meals or immediately afterwards. A sustained release preparation of iron can be tried if symptoms persist. In case this too fails parenteral iron therapy is required (For details refer to chapter on 'Mirror Mirror on the wall which is the best Iron of them all'). Persisting Cause for Anemia: If there is a persistent hemorrhage, occult or obvious it can lead to a partial or complete failure of response to iron therapy. An occult cause is often in the gastrointestinal tract which requires evaluation in the form of stool examination and GI endoscopy. An obvious cause of hemorrhage like hemorrhoids or fissure in ano should be treated appropriately. Hookworm infestation still remains a major cause of persisting anemia, especially in the rural pregnant women and women of lower socioeconomic strata. Less common causes of failure of response to iron are a. Disorders affecting bone marrow function like i. ii. Chronic Infections e.g. malaria, urinary tract infection, tuberculosis. Worm infestations

iii. Chronic Renal Insufficiency. iv. Co existing B12 and Folate deficiency b. Malabsoption of Iron as in i. ii. c. d. e. f. Alimentary tract disease e.g. chronic diarrhea, irritable bowel syndrome. Occult Malabsorptive Disease.

Protein Calorie Malnutrition Improper administration of iron e.g. administration of Calcium and Iron together impairs iron absorption. Undiagnosed hypothyroidism. Bleeding hemorrhoids and fissure.

In these situations the underlying cause for lack of response should be treated and in case of malabsorption parenteral iron therapy is to be considered. References 1. 2. G. Richard Lee. Iron deficeincy and Iron deficiency anemia In. Wintrobe's Clinical Hematology. 10th Ed. Williams & Wilkins; 1998; 979 1010. Stoltzfus R.J. et al guide lines for the use of Iron Supplements to prevent and treat Iron deficiency anemia on behalf of the International Nutritional Anemia consultative group (INACG) Washington, 1998, International life sciences Institute press. Bitran J. D et al Megaloblastic anemia during pregnancy J Rprod Med 1977; 19; 186 192

3.

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Hemotherapy In ObG : When, why And How?

Dr. Shivaram C, Chief, Transfusion services, Manipal Hospital, Bangalore. One of the earliest documents on Blood transfusion by Andreas Libavius(1546-1616) reads as follows: Let there be a young man , robust, full of spirituous blood, and also an old man thin, emaciated and exhausted. Let the performer of the operation have 2 silver tubes fitting into each other. Let him enter the artery of the young man, and put in one of the tubes. Let him open the artery of the old man and put the female tube into it and then the two tubes being joined together the blood of the young man will pour into the old one as it were from a fountain of life, and all his weakness will be dispelled. The first recorded man-man transfusion transfusion was carried out by James Blundell, an English obstetrician who saved the life of a lady who was having severe post partum hemorrhage by transfusing the husband's blood at a time(1818) when even blood groups were yet to be discovered by Karl Landsteiner(1900). However, today we can no longer rely only on spirituality for safe blood, nor is husband's blood considered appropriate for the wife to avoid sensitization with paternal antigens. However, husband's can receive wife's blood since they don't give birth to babies! Blood safety has three elements. 1>Safe donor (Altruistic Voluntary blood donor) 2>Safe blood ( Good testing methodology-ELISA/NAT ) 3>Safe Transfusion by clinicians-the end users of blood. Why do women need blood ? According to a nationwide Indian study carried out by Tim Bray etal Adult recipients account for 87% of transfusions, and amongst the age group of 2534, 73% of transfusions were for women. Anaemia was listed as a reason for 60% of transfusions, surgery for 42%, acute haemorrhage for 26% and pregnancy for 16%. Seventy-four per cent of adult transfusions were inappropriate. According to another study in Bangalore (due for publication) 3 out of 4 deaths that took place in Bangalore as a consequence of Post Transfusion GVHD in 2005-2006 were caused by encouragement / acceptance of relatives' blood by Obstetrician / gynaecologists. Anemia among Indian women is a very common entity. According to a survey 52 % women have anemia and 17 % have moderate to severe anemia. MMR in India continues to be high. While the
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IMR has declined significantly over the years a proportionate drop in MMR is yet to be seen. Anemia is responsible for 14-24% of the maternal deaths, while bleeding during pregnancy is responsible for 16-26% of maternal deaths. Access to good quality blood / blood components coupled with its rational use can significantly contribute to reducing MMR in India. Comparison with rest of the world: The need for transfusion of red blood cells (RBC) during pregnancy and the peripartum period is fairly significant occurrence seen in 1% to 2% of all pregnancies in the developed countries. It has been estimated that RBC transfusions are given in 0.3% to 1.7% of vaginal deliveries, between 0.7% and 6.8% of cesarean deliveries, and in as much as 8.6% of cases of ruptured ectopic pregnancies.(Obstetrics & Gynecology 2004;104:1000-1004 ) Although no Indian data is forthcoming on this, blood usage especially whole blood usage in pregnancy / peripartum period is very common in India. Use of whole blood to reach that magical figure of 10 g% is probably unnecessary in majority of cases. As a general rule, only RBC transfusions should be given that too, only when absolutely necessary. This will minimize the risks of exposure to allogeneic blood products and risk of exposure to infections. Use of whole blood in pregnancy to correct anemia overburdens the already burdened heart. Use of whole blood for massive blood loss corrects anemia but leads to dilution of platelets and coagulation factors leading to complications of massive transfusion like coagulopathy, acute DIC. FRESH WHOLE BLOOD: Use of fresh blood to correct platelet deficiency and clotting factor deficiency (result of massive transfusion with whole blood) is not practically possible due to the volumes involved. Further, use of fresh blood necessitates screening by the less accurate Rapid/spot tests as opposed to the more accurate ELISA tests. Further, infectious agents like T.Pallidum can survive in fresh blood. Fresh blood upto 3 days old is more likely to have viable white cells and has been to shown to have greater chances of inducing Graft Versus Host Disease-a life threatening complication of blood transfusion. Fresh whole blood is a vestige of past transfusion practices when appropriate components were not available. American association of Blood banks has no indication for whole blood transfusion in modern medical practice. Causes of anemia 1> Increased red cell loss v Acute: trauma / surgical / obstetric haemorrhage v Chronic blood loss: GIT / urinary tract / reproductive tract / parasitic infestation / malignancy / inflammatory / hemolytic disorders 2> Decreased production of red cells v Nutritional deficiency iron / B12 / folic acid / malnutrition

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v Bone marrow failure v Renal failure (decreased erythropoietin production) v Chronic illness v Lead poisoning v Increased destruction of red cells v Infections bacterial / viral / parasitic v Hemoglobinopathies v Drugs-dapsone v HDN Acute Anemia It is the result of acute blood loss surgical / traumatic v Acute Blood Loss v Blood Vol decreased v Total Hb is decreased v O2 storage / transport / delivery decreased Decreased Hb X Decreased O2 saturation X Decreased Cardiac output = Diminished O2 supply to tissues in acute anemia. v Compensatory mechanism activated: v Restoration of plasma Volume v Restoration of Cardiac out put. v Stimulation of ventilation Chronic anemia v Continued blood loss - small quantities. v Nutritional deficiency v Hemoglobinopathies v Increased demand for red cells v Pregnancy / Lactation COMPENSATION v Cardiac output increased v O2 dissociation curve of Hb shifts to increase O2 release v Fluid retention Decreased Hb X Increased Saturation X Increased Cardiac Output =Maintains O2 supply to tissues.

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Management of Acute Anemia v Treat underlying cause(Iron/B12 etc) v Assess degree of oxygenation v Improve O2 supply if needed. v Transfuse ONLY RED CELLS, not whole blood, when O2 supply is inadequate. v Transfusion in megaloblastic anemia: Dangerous because of the co-existent poor myocardial function which could precipitate heart failure. v Immune anemias: Antibodies in patient's serum may hemolyse not only transfused red cells but patient's own remaining red cells. Management of Chronic Anemia v Exclude hemoglobinopathy v Identify & correct blood loss: Local bleeding / helminthic infestation. v Oral iron / B12 / folic acid v Consider and treat malaria v Review drug history NSAIDS / Dapsone / anticoagulants / marrow suppressive drugs Treatment of Severe decompensated Anemia v Treat infections v Give O2 by mask v Correct fluid balance v Transfuse red cells in the right dose along with a diuretic like frusemide. v It is not necessary to restore the normal Hb. v Raise it just enough to relieve the clinical symptoms (usually 8g/dL is sufficient). RED CELLS: When to Transfuse ACUTE BLOOD LOSS The primary treatment of acute blood loss is not blood. It is crystalloids / colloids. Upto 20% Blood loss v Give Crystalloids - Normal Saline / Ringer Lactate. v Volume needed for replacement is 2-3 times the volume lost. v Anticipate risk of fluid overload. Continued loss v Add colloids - 5% Albumin or hydroxyethyl starch. v Replace colloids volume for volume v 30 % Blood loss:
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v Use red cell concentrate (packed red cells) to correct volume & oxygenation. v If there is uncontrolled bleeding and laboratory evidence of coagulopathy add fresh frozen plasma. v If bleeding continues - consider platelets after investigations. v Use appropriate blood group switches when same group is not available. THRESHOLD FOR RED CELL TRANSFUSION: Historical Facts v MAYO CLINIC in 1900 proposed a target value of 8-10 g/dL. v CURRENT PRACTICE (NIH Consensus) is 7g/dL in the absence of disease 8-10g/dL in the presence of disease (cardiovascular disease / risk factors / elderly). Rate of fall of Hb is more important than the actual Hb value Healthy individuals tolerate Hb levels as low as 5g / dL RELATIVE EFFICACY Whole Blood v v v v v v v v Volume Haematocrit Red cell volume Increase in Hb% Platelets Complications Cost 350 ml 40% 160ml 1g/dl None More likely More Red cells 250 ( 350ml with Additive solution) 75% 190 ml 1. 3g/dl Minimal None Less likely Less

Unwanted plasma Plenty

LEUKO-DEPLETED RED CELLS : Why to use ? v Avoids treatment of multiple febrile transfusion reactions. v Prevention of CMV transmission v Prevention of allo-immunisation to leukocytes and platelets LEUKO-DEPLETED RED CELLS: When to use ? v Multiply transfused patients. v Multiparous women v Intrauterine transfusions v Exchange transfusions in newborn v Haemoglobinopathies-Thalassemia
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v Bone Marrow Transplantation v Leukemias,Solid tumours, other immunodeficiency states MASSIVE TRANSFUSION v Replacement of patient's blood volume in 24 hrs. v Transfusion of >20 units of red cells in 24 hrs. v Replacement of >50% of patient's blood volume in 3 hrs. v Replacement for blood loss >150ml/min in an adult. POTENTIAL COMPLICATIONS: v Thrombocytopenia v v Coagulopathy DIC

v Hypocalcemia v Hyperkalemia v Metabolic acidosis v Hypothermia THERAPY: Correct thrombocytopenia with platelets and coagulopathy with FFP. Cryoprecipitate may be used to replace fibrinigen or factor VIII. Warming of blood is indicated only in case of massive red cell transfusions. Modifications of routine practice can minimise the need to transfuse red cells, v Checking for and correcting anaemia before planned surgery. v v Stopping anti-coagulants and antiplatelet drugs before planned surgery Minimising the amount of blood taken for laboratory samples.

Current Transfusion Trigger for Red cells v Local guidelines are important; local factors must be taken into account. v Large randomised clinical trial ( Level I evidence) in critically ill patients demonstrated that a restrictive transfusion policy : aimed at 70-90 g/l is at least equivalent, and possibly superior, to a liberal policy maintaining Hb at 100-120g/l.

v In patients without cardiovascular disease, esp. younger patients, maintain haemoglobin levels in the range 70-90 g/l. v In patients known to have or likely to have cardiovascular disease, (hypertension / diabetes / elderly), maintain haemoglobin in the range 90-100g/l.

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GENERAL GUIDE: In normal healthy individuals, a transfusion threshold of 70g/l is appropriate. (critical level of 40-50g/l) Transfusion In Obstetric Hemorrhage v Monitor CVP and arterial pressure. v Take samples for transfusion and coagulation screen. Order at least 6 units of red cells. v Do not insist on cross matched blood if transfusion is urgently needed. v Warm the resuscitation fluids. v Transfuse red cells as soon as possible. Until then: - crystalloid, maximum of 2 litres colloid, maximum of 1.5 litres -

v Restore normovolaemia as priority, monitor red cell replacement with haematocrit or Hemoglobin. Note that the correct increment can be obtained only 24 hours post transfusion in case of red cell transfusion and 1 hour post transfusion in case of platelets. v Use coagulation screens to guide and monitor use of blood components v If massive bleeding continues, give FFP 1 litre, cryoprecipitate 10 units while awaiting coagulation results. Cryoprecipitate will need to be repeated twice a day till bleeding is under complete control. Appropriate use of Blood components in bleeding patient FFP: indications and dose for haemorrhage v More than 1 blood volume replaced or Prothrombin time prolonged with INR >1.5 and/or continued blood loss Dose: 15 ml/kg or 1 Litre (4 packs) for adult of 60 kg Platelets: Indications and dose for haemorrhage v Platelet count below 50 109/l (<50,000/ul or cmm), in the presence of bleeding. v In the absence of bleeding and or fever and if there is no planned invasive procedure a platelet count of 10,000/ul or cmm is acceptable. Drop in Platelet below this level necessitates transfusion with platelet concentrates. v Dose: 4-6 platelet concentrates or one unit of single donor(apheresis) platelets. Cryoprecipitate: Indications and dose for haemorrhage v Useful only if the fibrinogen is particularly low(<1g/l) or <100mg/dl. v Early use of FFP may avoid the need for cryoprecipitate v Give 10 units initially and repeat based on fibrinogen estimation v Note: Cryoprecipitate is not available from all blood centres. 5 units of FFP (1000-1250 ml) contains, typically, the same quantity of fibrinogen as 10 units of cryoprecipitate (approximately 150-250 ml) v Dose: one unit/5 kg body weight or 10 units in the adult.
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Intrauterine Transfusion for correction of pre-natal anemia Foetal distress is diagnosed by diminished middle cerebral artery blood flow detected by ultrasonography. Rising atypical(antiD) titres coupled with foetal distress also constitute an ominous sign. Management : Transfuse red cell concentrate of group O Negative to achieve the desired target Hb level. Red cells used for transfusion must have a hematocrit, as high as possible, preferably 90%, although in practice, blood banks can seldom concentrate red cells beyond a hematocrit of 80%. Red cells must be sickle cell negative and also negative for CMV infection. CMV negative blood is difficult to find in our country where majority are exposed to CMV infection, at some point in their lifetime. An alternative is to use Leukofiltered red cells. Red cells must be filtered using a leukodepletion filter for red cells, which is able to remove more than 99.99% of leukocytes and the CMV within them. Filters are expensive costing about Rs1200/-but well worth preventing CMV infection in the foetus. Red cells used for IUT must also be irradiated with Gamma rays (Dose 25 Gy or 2500 rads) to prevent post transfusion GVHD. Use of buffy coat removed or washed red cells is an inexpensive, but much less effective alternative to leuko filtration. It is only effective in prevention of febrile transfusion reactions, not in prevention of CMV infection. It is desirable to use red cells less than 7 days for prevention of hyperkalemia and acidosis in case of IUT and neonatal exchange transfusion. This is perhaps the only genuine exception for using fresh blood in transfusion practice. Time limits for infusing blood components : All blood components must be transfused as soon as they are received from the blood bank without warming them. All blood and blood components must be transfused at the same temperature at which they are issued without warming. Warming of blood using water baths, pillows, leaving at room temperature for 30 minutes are all equally erroneous. Massive transfusion in the adult and exchange transfusion in the newborn are the only exceptions. Blood is warmed using a blood warmer in these conditions. Ordinarily one unit of red cells / whole blood must be transfused in 2 hours, never beyond 4 hours. Fresh Frozen Plasma being more fluid, may be transfused over 20-30 minutes after thawing at 37 C in a sterile water bath. Likewise, cryoprecipitate and Platelet concentrates may be transfused quickly over 20-30 minutes. It is important to use a new standard blood filter (clot screen filter) with a pore size of 170 microns for transfusion of red cells / whole blood. The same filter needs to be used for platelets, FFP and cryoprecipitate as well. Transfusions must be documented and monitored at start of transfusion, 15 minutes post transfusion and finally at the completion of transfusion. More frequent monitoring may be necessary in case of sick patients.

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In emergencies, the following may be used: v Uncrossmatched group specific blood v Cells - group O of appropriate Rh type v Plasma group AB (which lacks antibodies) Conclusion: Anemia and blood loss are very common in women. Transfusion trigger for red cells in the absence of cardiovascular risk factors (hyperetension / diabetes / elderly) is 7g/dl. In presence of this, transfuse to maintain a higher level 8-9g/dl. Platelets need to be given only when the count falls below 10,000/ul in asymptomatic patients. However, in the presence of bleeding or planned invasive procedure, a count of 50,000/ul is desirable. Use of FFP in coagulopathy in the absence of bleeding is guided by prothrombin time and use of cryoprecipitate by fibrinogen levels. Fresh whole blood is not a substitute for blood components. Avoid fresh blood and relative's blood to prevent GVHD. Transfuse blood without warming using a filter within a maximum time of 4 hours. Even tested blood is not safe. Rational use of blood is therefore recommended. Consent for transfusion of blood / refusal of transfusion along with alternatives offered needs to be documented. References: 1. 2. 3. 4. 5. 6. 7. 8. Transfusion Medicine ,Volume 13 Issue 1 Page 17 - January 2003 T. J. Bray, P. Salil, H. A. Weiss, J. D. H. Porter (2003). Transfusion medicine in India: a survey of current practice Policy Barriers Preventing Access to Emergency Obstetric Care In Rural India Dr Dileep V Mavalankar.,Public Systems Group,Indian Institute of Management, Ahmed) Obstetrics & Gynecology 2004;104:1000-1004 Modern Blood Banking and Transfusion Practices, Denis M harmening Transfusion Medicine, Jeffrey McCullough. Technical Manual, AABB BCSH guidelines for transfusion triggers. Shivaram C, Guha's Textbook of Neonatology.

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CONSENT FOR DIRECTED DONATION

1. 2.

I have been informed that transfusion between first degree relatives carries with it the risk of a fatal (life threatening) complication called Post Transfusion -Graft Versus Host Disease. I am also told that although rare (incidence 0.1 % or one in 1000 transfusions) this complication is more likely to occur with relatives' blood, and is almost always fatal and treatment for this is almost non-existent. In light of this, I have been counseled by the blood bank staff named below, NOT to use relatives blood. I have fully understood the risk of GVHD. Further, I have weighed the risks of contracting HIV/ Hepatitis from an unknown donor in the window phase/incubation period versus Post-Transfusion GVHD from a relative donor. I understand PT-GVHD is more likely to be fatal than HIV/Hepatitis resulting from blood transfusion. Despite knowing all this, I still prefer that I / my patient receive blood from our relative only. This has been explained to me in (language)________________________

3. 4.

5.

I shall not hold the Blood bank/consultants/hospital responsible in the event of my/ my patient's death due to post transfusion Graft Versus Host disease.

Signature: Relation to patient

Sign of Blood bank Staff Name of staff:

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Anaemia in Pregnancy-A teaching hospital experience

Dr. K . V. Malini M.D., D.G.O., MICOG, PGDMLE, Professor, Dept of Obstetrics and Gynaecology, Bangalore Medical College, BANGALORE.

Anaemia is the most neglected and the commonest medical disorder seen in pregnancy. It has a varied prevalence, etiology and degrees of severity in different populations, being more common in developing countries. This nutritional problem keeps the woman in high risk category as she is prone for many complications like PIH, sepsis, prematurity & low birth weight babies( Tyagi et al1985). Several studies have reported association of anaemia with maternal and foetal morbidity. This study is undertaken to assess the magnitude of the problem and its impact on maternal and foetal outcome. Material and Methods A retrospective cohort study was conducted in Vani Vilas Hospital attached to Bangalore Medical College, a premiere teaching institute. It is a 450 bedded referral maternity hospital catering to the needs of population comprising mainly of low socio-economic group. The study was undertaken for a period of three months from October December 2006 and comprised of retrospective analysis of 1380 singleton pregnant women admitted in labor with anaemia. Women with multiple pregnancies and antepartum haemorrhage were excluded from the study. The information regarding age, parity, level of Haemoglobin were collected from the records. Haemoglobin was estimated by Sahli's method in our institute. Whenever complete haemogram and stool examination were done, the reports were noted down. Women were categorized into mild, moderate, severe and very severe group depending on Hb percentage as per ICMR guidelines, i.e., mild 10.9 to 10gm, moderate 10 to 7 gm, severe - < 7gm and very severe - < 4gm. Various maternal and foetal complication were studied under these four groups. Standard Normal Variate test (Z Test) and Chi-square test were applied to the complication observed under these groups. Observations The prevalence of anemia among obstetric admissions in our study was 52% (1380 / 2654). Out of 1380 women with anaemia, only 423 were booked and 957(69.4%) were unbooked. Most of the women belonged to low socio-economic status. The commonest type of amaemia was Iron deficiency anaemia as evidenced by the peripheral smear.

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Most of the women belonged to moderate group as shown in the graph below.
Distribution of cases n =1380 10% 1% 30% Mild (426) Moderate (810) Severe (132) Very Severe (12)

59%

Anaemia was more common in multi parous women as compared to primis.

Parity n = 1380 43%

Primi (588) Multi (782)

57%

Most of them were in the age group of 20 29 years

Age distribution Age in years < 19 20 - 29 30 and above Number of cases 174 1125 81 Percentage 13% 82% 5%

Various complications noted were :

Complications PTD IUGR Birth Asphyxia MSAF IUD PIH PPH Forceps delivery CCF Sepsis Maternal Death 1 12 6 45 3 3 Mild Moderate 114 222 6 30 18 111 Severe 21 12 3 27 12 12 1 12 1 1 1 2 1 Very Severe Total 135 279 12 60 30 129 3 24 1 1 2

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Foetal complications like low birth weight (< 2.5kg) babies, preterm deliveries, MSAF, birth asphyxia, intrauterine deaths and maternal complications like pregnancy induced hypertension were all seen more in severe and very sever anaemia group as shown in the graphs below.
Low Birth Weight Babies n =279

PreTerm Deliveries n = 135

35% 30% 25% 20% 15% 10% 5% 0%

20.00%
Mild (80) Moderate (149) Severe (46) Very Severe (4)

15.00% 10.00% 5.00% 0.00%

Mild (31) Moderate (86) Severe (16) Very Severe (2)

Birth Asphyxia n = 12

MSAF n = 60
18% 16% 14% 12% 10% 8% 6% 4% 2% 0%

3% 2%

Mild (3)
2% 1% 1% 0%

Moderate (6) Severe (3) Very Severe (Nil)

Mild (5) Moderate (40) Severe (13) Very Severe (2)

Intra Uterine Death n = 30

18% 16% 14% 12% 10% 8% 6% 4% 2% 0%

PIH n = 129
18% 16% 14% 12% 10% 8% 6% 4% 2% 0%

Mild (3) Moderate (20) Severe (5) Very Severe (2)

Mild (25) Moderate (80) Severe (23) Very Severe (1)

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Forceps Delivery n = 24

9% 8% 7% 6% 5% 4% 3% 2% 1% 0%

Mild (6) Moderate (14) Severe (3) Very Severe (1)

There were three cases of atonic PPH, seen in severe and very severe anaemia group. Number of forceps deliveries were also more in severe anaemia group. There were two maternal deaths, one as a result of CCF and the second due to sepsis. Discussion From our study, it is evident that anaemia is still widely prevalent and is the commonest preventable medical disorder found in pregnancy. The global prevalence in non-industrialized countries varies between 35-75%, average being 56% (WHO in 1997). In our study, the prevalence was 52%. The relative prevalence of moderate and severe anaemia in our study was almost comparable with ICMR data. But, the number of mild anaemia cases were more in our study and the number of very severe anaemia cases were more in ICMR study.
Groups Mild Moderate Severe Very Severe ICMR 13 % 57 % 12 % 18 % Our Study 30 % 59 % 10 % 1%

Quite a significant number of women were 19 years and below (13%). Most of the women belonged to low socio-economic status and were unbooked. Nutritional deficiency was the commonest cause. There were no haemolytic anaemia or haemoglobinopathies in our study during this study period. Though severe and very severe anaemia cases formed a small group, most of the maternal and foetal complications were seen in this group. Since complications were many and each patient had more than one complication, Standard Normal Variate test (Z Test) and Chi-square test were applied to all the complications seen in mild and moderate anemia groups and sever and very severe anaemia groups. It if found that all the complications were higher in the latter group. (Here p = 0.708) SE of p = ( pq)/n = ( x 0.3)/1380 = 0.0123 0.7 i.e., Z = (p P)/(( pq)/n) = (0.708 0.5)/0.0123 = 16.26
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which is much more greater than 3. hence, it can be firmly stated that all the complications were dependant on severity of anaemia and more in women in severe or very severe anaemia group. There were total of 10 maternal deaths during study period, out of which two were due to anaemia. One patient died as a result of CCF secondary to severe anaemia and other died due to sepsis with very severe anaemia. One of our patients had severe infection of episiotomy wound. Her Hb% at admission was 4.2gm. She also had term IUD. Surprisingly in our study, there were no wound infections following LSCS. May be because of blood transfusion before and after surgery. Conclusion In spite of the advances in medicine, and development of modern technologies, nutritional deficiency anaemia continues to be the major health problem looming large over pregnant women in developing countries like India. The fact that most of the women were unbooked proves that either our women are ignorant about antenatal care or not having access to it. The incidence of anaemia can be decreased by maternal health education. Importance of antenatal care should be adequately stressed even if this means campaigning on a door-to-door basis. 'Catch them Young' i.e., efforts to identify and treat anaemia in the adolescent age group through school health programmes would be a better idea. Training and motivation of health workers could go a long way in early detection and treatment of this preventable, social malady at the grass root level. Acknowledgement Dr. Parvathi, Dr. Nirmala, Dr. Saraswathi for assisting in collecting the material. Mr. Joshi Statistician, Community Medicine Department, BMC Bangalore. References v Kishore singh et al-j obst.Gynaec.India.569:45:1995 v Koen MC et al J obst.Gyanec .India.569:45:1995 v Preety pandya-j.Obst .Gynaec. India.569:45:1993 v Rangnekar AG - J.Obst .Gynaec. India.172.43.1993 v Rathnam.S.S. Bhaskar Rao, S.Arul kumar -obst gynaec. for P.G.Vol.1 ii edition 1999 v Samir.A.R. International journal -obst .Gynaec. 1995 v Samir Roy J .Obst .Gynaec. India.743.42.92 v Sharma J B Nutritional Anaemia during pregnancy in non-industrialized countries, Progress in Obstetrics and Gynaecology, Studd Vol 15, 2003 v Suresh Deshpande - J .Obst .Gynaec. India. 37:49:1999 v WHO 1997
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Blood Banks

Dr. Swetha Arasu Bangalore About blood donation: 1. 2. 3. 4. 5. 6. 7.

Dr. Teena Thomas

Church of South India Hospital

Person above 18 years of age and over 45kgs. in weight can donate blood once in three months. A normal adult has five to six liters of blood in his/her body of which only 300 ml is used during blood donation. This blood is replaced by the body within 24 to 48 hours. No special diet, rest or medicine is required after blood donation. The donor should not have taken any medicine in the last 48 hours. The donor should not have contacted jaundice in the previous three years. Every donor is given a medical checkup prior to donation to see if he/she is medically fit and doesn't suffer from anemia, high blood pressure etc. The donor cannot contract AIDS or any other disease by donating blood.

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Transfusions for Anemia Tread with Caution

Dr. Tanya, Dr. Srividya, Dr. Prakash K. Mehta Bhagwan Mahaveer Jain Hospital, Bangalore. Introduction : Anemia contributes to significant morbidity and mortality in India. Up to 80% of Indian women are anemic. Factors contributing to anemia include nutritional deficiency in prepubertal and pubertal age group, frequent child birth in reproductive age group and menorrhagia in peri-menopausal age group .Among the management options blood transfusion plays an important role. However, transfusions need to be given with care and caution. Here is a case report of a patient who underwent hysterectomy for DUB. Case : Mrs. X, a 35 year multipara was referred to Bhagwan Mahaveer Jain Hospital for tertiary care with history of undergoing TAH for DUB four days prior to admission. Patient apparently had no pre-operative or intraoperative complications. Postoperatively patient was transfused 1 pint O positive whole blood, following which she developed vomiting, breathlessness and decreased urine output. Post transfusion a fall in Hemoglobin levels was noted and hence she was transfused 2 more units or O positive whole blood. Patient's condition continued to deteriorate. She became hypoxic and had renal failure following which patient was referred to our centre. Patient is P2L2 with last delivery 15 years back and underwent tubectomy .She had menorrhagia since 2 years. Her past and family history were not significant On Examination : :General condition : poor, Afebrile, Pallor++, Heart Rate - 60/min ,Blood Pressure - 140/90 mmHg, RR - 38/min SP02 84%, CVS : S1S2,RS : scattered b/l crepitations +, P/A Soft wound healthy BS+ , PV - vault healthy, no bleeding PV. Catheter in situ no urine draining. Patient was admitted to ICU. Investigations showed Hb 5.9gm%; PCV 18.4%; Peripheral smear features of Hemolysis, Blood urea 167 mg %; Serum Creatinine 2.6 mg%; Na 137 meq/l; K+ 3.4 meq/l; RBS 105 mg%, USG done revealed Normal study. A diagnosis of ARF and hemolysis due to? transfusion reaction? sepsis considered. A search was made for the precipitating factor Based on history & investigation reports, mismatched transfusion was considered to be a greater probability. Samples were sent to blood bank for blood group investigations. On direct matching the blood group was revealed as O positive. However, on reverse cross matching, she was found to have Bombay blood group. In view of anuria and rising creatinine, patient was started on hemodialysis. In view of extreme rarity of Bombay blood group, extreme difficulty encountered in obtaining cross matched blood. Only 3 pints of blood could be arranged one from BMJH blood bank, one from Manipal and one from Mumbai. We could arrange only 3 pints of Bombay Blood group for the patient. Patient was also given erythropoietin injections in view of limited availability of blood and with a hope that if the patient survives for a week, then this could take care of anemia. In spite of all measures, patient's condition continued to deteriorate; she
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developed ARDS and needed ventilatory support. Patient developed Generalized Tonic Clonic convulsions. CT scan revealed multiple hypodense lesions with hyperdense lesions in Left Frontoparietal and right parietal region and gross edema -suggestive of venous infracts. Patient was started on steroids & epsolin. 24 hours later patient arrested and in spite of following all ACLS protocol, she could not be revived. Discussion: Individuals with the rare Bombay phenotype (hh) do not express substance H (the antigen that defines blood group O) on their red blood cells, and therefore do not agglutinate (bind with) A or B antigens of the ABO blood group system. Instead, they produce antibodies to H substance (which is present on all red cells except those of hh genotype) as well as to both A and B antigens, and are therefore compatible only with other hh donors. This rare group was first identified in Bombay and hence the name. Transfusion of 'O' group blood to these persons would result in immediate red cell lysis because of the presence of anti H antibodies in the serum of Bombay Blood Group patients. Therefore blood from only a Bombay Blood Group individual should be transfused to a Bombay Blood Group recipient. Given that this condition is very rare to begin with, any person with this blood group who needs an urgent blood transfusion will probably be unable to get it, as no blood bank would have any in stock. In the above case morbidity could have been prevented by avoiding blood transfusion. Adequate preoperative correction of anemia by hematinics, avoiding blood transfusion for treatment of mild to moderate anemia goes a long way to prevent such mishaps References: Handa V, Oza RM, Patel RZ, Zanzarukiya BB, Mukherjee RA. The Oh (Bombay group)phenotype.J Indian Med Assoc. 1984 Dec;82(12):446-7.

The Bombay group

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ANAEMIA AND PREGNANCY CASE REPORT

Dr. Premila Phillips, Dr. Sandhya Toppo Church of South India Hospital, Bangalore CASE REPORT: Reporting a case of severe anaemia in a primi, 37wks and 5days gestational age, with preeclampsia and intrauterine growth restriction in latent labour. v Mrs. ST, a 22 year old, Primi, was referred to C.S.I. hospital, Bangalore on 24.11.06 with complaints of amenorrhoea of 37 weeks, swelling and pain of both feet for the past 3-4 months and shortness of breath on exertion of 2 months, worsening gradually to breathlessness even at rest. There was no history suggestive of impending eclampsia. v She has had 4 antenatal checks at a private clinic. v At 27 wks, she was treated for threatened preterm labour. v At 30 wks, she was treated for UTI. BP recorded at that time was 130/90 mmHg. v At 34 wks, she was started on Tab. Alphadopa 250 mg bd, but no record of BP available. Her hemoglobin at 34 wks was 4.5 g/dL for which she was treated with oral iron. Her USG at 34 wks was reported as single live intrauterine pregnancy of 29 wks with moderate oligohydramnios (AFI-6.5 cm). Placenta fundal and posterior in position. No obvious anomalies. ? IUGR. v At 37 wks. her BP was 180/80 mmHg. She was also pale and breathless and hence referred the same day to our hospital. v The patient does not give any history of menorrhagia or blood transfusions in the past. ON EXAMINATION She was moderately built and moderately nourished. She showed gross pallor, was breathless and had puffiness of face and extremities. Her pulse rate was 112/min and BP 160/90 mmHg. Her JVP and DTR were normal. Her cardiovascular systemic examination revealed a haemic systolic murmur which was heard all over her precordium. On abdominal examination there was mild abdominal wall edema. Uterus 32 wks size, relaxed, cephalic presentation and fetal heart sounds were regular. On pelvic examination, cervix was 75% effaced and os 3 cms dilated with the vertex at 0 station INVESTIGATIONS Hemoglobin 3.1g/dL PCV 13.8% Platelets normal Peripheral smear revealed microcytic hypochromic anaemia. Reticulocyte count was 3 %, Total.bilirubin 1.16mg/dL suggesting mild haemolysis.
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Serum.albumin was 1.7g/dL S.Uric acid was 6.2mg/dL. The renal function tests and liver enzymes were normal. Urine showed albuminuria of 2+ and 50-55 pus cells/hpf . Ultrasonogram: At 37 wks showed a single viable fetus corresponding to 31 wks. Total anhydramnios with a expected fetal weight of 1550+/-135 gms. NST Reassuring. MANAGEMENT 3 units of packed red cells were transfused and labor was accelerated with oxytocin. Liquor was clear. II stage of labour cut short with outlet forceps because of poor maternal efforts and anaemia. Prophylactic prostadin given at delivery of anterior shoulder. A male baby of 1.7kg with good apgars was extracted. One unit of packed red cells and one unit whole blood transfused postnatally. Post natal period was uneventful. BP was 130-150/80-100 mmHg on antihypertensive medication and patient was discharged on the 5th day. Her hemoglobin was 8.7 g/dL at discharge. She was advised to continue oral iron, calcium, protein and antihypertensive medication and return for follow-up after 3 days. COMMENT Anaemia as a factor in pregnancy and childbirth complication kills 585,000 women annually the worldover. In India anaemia is the commonest medical disorder seen in pregnancy with an incidence of 40-70%. 85% of Indian women are anaemic due to iron deficiency anaemia. It is a major contributing factor for maternal / perinatal morbidity and mortality in our country. Poverty, illiteracy and ignorance lead to malnutrition and in turn anaemia. Severe anaemia in pregnancy is associated with a high incidence of pregnancy induced hypertension, intrauterine growth retardation, intrauterine death and preterm labour. Education and elimination of poverty would go a long way in eradicating this preventable disorder. Women in the reproductive age should be advised regular antenatal checks, prophylactic haematinics and proper balanced diet rich in bioavailable Iron.

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PUBERTY MENORRHAGIA A CASE REPORT

Dr. Arpitha Deepak Singh, Dr. Nita Vasisht, Church of South India Hospital, Bangalore CASE v 19yr old, Miss Poornima has had her primary education and is a tele-caller by occupation belongs to middle socio-economic status. She has two siblings aged 16 and 13yrs (sisters, both studying). Her father is a driver by occupation and her mother is a housewife. HISTORY OF PRESENTING ILLNESS v Poornima presented to our hospital on 30-10-2006 with complaints of continuous bleeding P/V since 30.09.2006. This was the first episode of abnormal menstrual bleeding. For this, she sought medical help at a local clinic, where she was prescribed hematinics only. Patient also gave history of loss of weight since one month, and related the same to the excessive bleeding P/V. She had no H/O amenorrhoea prior to the current menorrhagia cycle. She gave no history of giddiness / nausea / vomiting / chronic cough / fever / loss of appetite / bleeding per rectum. MENSTRUAL HISTORY v Patient attained menarche at 13yrs of age. Her cycles initially were irregular and of the pattern 1wk/5-6months, with a normal flow. Following this, she has been having regular cycles, 4days/28-30days, with a normal flow, with no clots / dysmenorrhoea. Her last menstrual period was on 30-09-2006. PERSONAL HISTORY v Patient is unmarried and not sexually active. Patient is a poor-eater as per her mother's history. She had not been dewormed in the recent past. No history of previous surgeries / blood transfusion / tuberculosis / drug intake / bleeding disorders. FAMILY HISTORY v No similar history in the family. Her mother and the older of her two sisters have regular and normal cycles. There is no history of bleeding disorders in the family. ON EXAMINATION Patient was moderately built, poorly nourished with a Height of 153cm, weight of 33kg, with a BMI of 14.6. Her vitals recorded were, Temp: 98.6F, Pulse rate: 100/min and BP: 120/80mm Hg. Clinically breasts and thyroid were normal. No bruises / petechiae / pedal edema were found on examination

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v Pallor: +++ (Conjunctiva / tongue-pale) v RS: Clear CVS: Flow murmur + JVP: Raised v PA: Soft, no tenderness / organomegaly v PV: Bleeding + v PR: NAD CLINICAL DIAGNOSIS v 19ry old poorly nourished girl with severe anaemia (secondary to menorrhagia) in early failure INVESTIGATIONS v Blood groping/typing: O Positive v Hemoglobin: 3.4g/dl v PCV: 12.1% v TC: 5,600cells/cmm v DC: P75%L24%E01% v Platelets: 2.2L/cmm v TSH: 1.75mcIU/ml v BT: 2'30" CT: 12' v Urine R/M: WNL v Stool: No ova v Ultrasonography: Uterus AV, measures 71 x 29 x 48mm, ET: 4mm Myometrim-N B/L ovaries N PERIPHERAL SMAEAR v Very pale smear showing a marked paucity of erythrocytes, adequate platelets & somewhat scanty leucocytes v RBC's are very anisocytic, anisochromic and mildly poikilocytic with no visible hemoparasites v A few, single Howel Jolly bodies are seen v Macrocytes, microcytes, elliptocytes and abnormal shapes are seen v WBC's and platelets are morphologically unremarkable v IMPRESSION: ANAEMIA, VERY SEVERE, CONSISTANT WITH SEVERE IRON DEFICIENCY OR CHRONIC DISEASE, MILD LEUCOPENIA

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FINAL DIAGNOSIS v 19ry old malnourished girl with severe iron deficiency anemia, in early failure TREATMENT GIVEN v Tab. Tranexaemic acid 500mg 8th hourly x 3days v Tab. Norethisterone 12th hourly x 21days v Three units compatible packed cells transfused v Oral iron x 3months v Deworming done v Patient counseling regarding condition and modality of treatment v Health education regarding diet, general health measures AT DISCHARGE v Sense of well-being expressed by patient v Repeat Hemoglobin: 9.6g/dl LESSONS LEARNT v Anaemia is the most common and treatable condition affecting all age groups, more so the adolescents and pregnant women in our country v Education and awareness regarding the condition and its prevention, a key factor in changing the current scenario v Regular health camps, regular ANC's to detect/investigate the condition early and treat adequately, a must v Golden rule to be remembered and to be reinforcedPREVENTION IS BETTER THAN CURE!

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Obstetric Catastrophe leading to anemia

Dr.Bhavana Mishra, Dr.Shah Prarthana, Dr. Prakash K. Mehta Bhagwan Mahaveer Jain Hospital, Bangalore. Introduction: Antepartum hemorrhage is still an important cause of maternal death in the developing countries. The major risk of placenta previa is severe vaginal bleeding and consequent morbidity related to hemorrhagic shock and prolonged hypotension. Placenta previa is overwhelmingly a problem of parous women. While it occurs only once in 250 nullipara, it is more frequent in grand multipara and women with previous cesarean delivery. Here is an interesting case of BOH, previous LSCS with twin gestation and placenta previa. Case : Mrs .Y , a 25 yr old G3P2L0D2, was referred to Jain Hospital at 26+5 wks with twin gestation & APH. She presented to us on 15.12.06 with heavy bleeding per vaginum since that morning associated with passing of clots and mild abdominal pain. She appreciated fetal movements well. Obstetric history: ML: 6 years, non consanguineous, G3P2L0D2 - G! : 4 yrs back, had jaundice antenataly, vaginal delivery at term, baby died 2 hrs later, cause not known. G2: 2 yrs back, H/O placenta previa & LSCS for IUD at 7th month. She had PPH and was transfused 5 units of blood. G3: LMP: 12/6/06 EDD: 19/3/07. H/O spotting twice in the 2d trimester, diagnosed as placenta previa. When she had the third episode, she was admitted to a near by hospital where she was transfused one unit of whole blood and discharged. On examination: Pallor ++, Tachycardia (HR- 110/min), BP 100/60 mmHg. P/A examination vertical scar+, uterus 32 wks size, with multiple fetal parts, no scar tenderness. FHR +/+. PS: Bleeding ++ Clots +. NST: Reactive for both fetuses. Scan done to confirm diagnosis of placenta previa and estimation of fetal weight. Hemoglobin: 7.2gm%. Patient underwent emergency LSCS in view of BOH, previous LSCS, placenta previa with twin gestation after rescue steroiding and arranging for blood. Lower segment thinned out and vascular. Placenta cut through and two male babies weighing 870 and 850 grams extracted. Both babies shifted to NICU. The first twin had TEF Type II and expired on fourth post natal day. The second twin was ventilated stabilized and finally discharged at the end of 6 weeks. Patient transfused 2 units of whole blood and repeat hemoglobin was 8.4gm% hence no further transfusion given. She was discharged on day 6 with advice to continue haematinics. Discussion: The dilemma we faced while managing this case was about the decision to go ahead and deliver the babies. There were no records available regarding patient's previous pregnancies. Considering her H/O previous neonatal death and IUD, a decision had to be made, especially in
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face of bleeding placenta previa, twin gestation and anemia. Adequate support from blood bank is pivotal in management of patients with late pregnancy bleeding to avert maternal morbidity and mortality. Facilities for immediate cesarean section, neonatal resuscitation and intensive care are critical for the management of such patients. Early transfer of patients to a tertiary centre results in a better maternal and neonatal outcome. Bibliography: Archibong EI, Ahmed el SM. Risk factors, maternal and neonatal outcome in major placenta previa: A prospective study. Ann Saudi Med. 2001 May-Jul;21(3-4):245-7.

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A CASE OF ANAEMIA DUE TO THYROID DEFICIENCY Dr. Parimala Devi

CASE HISTORY: Patient aged 32 yrs., P2 with 2 LSCS was often treated for anemia. She underwent Cesarean Section for 1st pregnancy with preterm PROM as indication. She did well in the postnatal period. However, she would always have excessive menstrual bleeding lasting for 5 to 7 days and was treated symptomatically. Soon she dropped her hemoglobin and was given iron supplements. She got an IUCD inserted but got it removed within a few months due to menorrhagia. She was pregnant again and underwent repeat LSCS. Post operative period was uneventful. Soon she resumed periods. She again had menorrhagia and was put on progestogens. USG showed normal study. She never improved with routine line of management, and she became quite pale and blood transfusion was given to correct hemoglobin. Detailed biochemical test revealed THYROID DEFICIENCY and correction of the same controlled the menorrhagia. Patient improved dramatically. KEY POINTS: Anemia secondary to hypothyroidism is common. About 10 12% of DUB is due to hypothyroidism. It is therefore important to investigate a case of resistant anemia, for thyroid deficiency too.

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