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By  Prof. Dr. Asmaa AbdulAziz
Definition: The haemoglobinopathies are inherited disorders of haemoglobin  synthesis  (thalassaemias) or  structure  (sic...
These disorders result in errors in oxygen-carrying  capacity of haemoglobin . Diseases linked to genetic predisposition a...
Sickle cell and thalassaemia are inherited disorders that are passed on from parents to children through unusual haemoglob...
<ul><li>Individuals with  Haemoglobinopathy  are:  </li></ul><ul><ul><ul><li>either  healthy carriers ( trait  ) i.e. unaw...
Who can be a carrier? Anyone can be a healthy carrier. This means you are more likely to be a carrier if your ancestors ca...
The diagram below shows the chances (for each pregnancy) of two carrier parents having a child with a sickle cell or thala...
If the mother is anemic & the father is healthy carrier 50% of the off springs are carriers and 50% is anaemic
Sickle Cell is a condition that affects the normal oxygen carrying capacity of red blood cells.  When the cells are de-oxy...
The term sickle-cell disease is preferred because it is more  comprehensive than sickle-cell anaemia.
 
 
2-The clinically significant haemoglobinopathies are listed in following  Table
<ul><li>In children, sickle-shaped red blood cells often become trapped in the spleen, leading to a serious risk of death ...
Thalassaemia Major  : It is the most severe form of thalassaemia, results in the inability of the body to produce haemoglo...
The impacts of genetic disorders on infectious diseases (Malaria & Sickle cell disorders) Many studies  showed reduced mor...
<ul><li>The   sickle   cell   trait  confers a selective   advantage: resistance to severe   malaria .  The mechanism of t...
Prevalence of haemoglobinopathies   The World Health Organization (WHO) estimates that globally at least : approximately  ...
 
Prevalence of Sickle cell disorders
 
SITUATION in Africa The highest prevalence of sickle-cell trait  is in parts of Africa & among people with origins in equa...
Over 300 000 children are born each year with a severe haemoglobinopathy. 30%  are born with thalassaemia syndromes while ...
 
The situation in KSA: In a study carried in KSA ,the incidence of hemoglobulin S for the studied neonates was 14.4% and ra...
<ul><li>In Bahrain Genetic disorders of haemoglobin are prevalent. In a study of the hospital population covering </li></u...
<ul><li>Sickle-cell disease in Bahrain and Saudi Arabia presents special features. SCD in this area is clinically mild, an...
National Control program for haemoglobinopathies: The development of appropriate national control programme  is now accept...
<ul><li>The control program depends on the characteristics & the requirements of individuals with haemoglobinopathies. </l...
National Control program for sickle cell diseases 1- setting up  sickle-cell screening  and genetic counseling programmes ...
<ul><li>The antenatal screening programme </li></ul><ul><li>Parent screening for sickle cell and thalassaemia  aims  to  <...
ANTENATAL SCREENING   Pregnancy Offer screening Blood sent to laboratory for haemoglobinopathy Screen Positive results Inf...
Premarital diagnosis  : In the Saudi society, consanguineous marriages are high (60%).  Recently, the Saudi government int...
<ul><li>NEONATAL SCREENING   </li></ul><ul><li>The newborn sickle cell screening is part of the existing bloodspot  progra...
<ul><li>In UAE, a standard form for neonatal screening is issued to every baby born hospital, where 99% of deliveries occu...
<ul><li>Genetic counseling </li></ul><ul><li>It is the process through which knowledge about the genetic aspects of illnes...
A survey of 500 parents, with children who have a genetic diseases was carried, to find their knowledge about genetic dise...
<ul><li>Pneumococcal diseases in children with  Sickle cell disorders  : </li></ul><ul><li>Children with sickle cell anaem...
Age distribution of pneumococcal bacteremia in children with sickle cell disease or HIV and healthy children at Boston Med...
<ul><li>Pneumococcal diseases  in sickle cell children  include </li></ul><ul><li>Pneumonia & bronchitis </li></ul><ul><li...
<ul><li>The Risk Factors for Recurrent Pneumonia in Children which include :  </li></ul><ul><ul><li>Sickle-cell diseases <...
<ul><li>The causative agents :  Streptococcus pneumonia  </li></ul><ul><li>Children under 2 years old are at highest risk ...
Pneumococcal  vaccine  can help prevent serious Pneumococcal disease, such as pneumonia, bronchitis meningitis and septice...
There are two types of Pneumococcal vaccine: 1- Pneumococcal polysaccharide vaccine (PPV)  contains purified capsular poly...
<ul><li>Pneumococcal polysaccharide vaccine (PPV) </li></ul><ul><li>Adults  develop a good antibody response to a single d...
Pneumococcal conjugate vaccine (PCV) The antibody response in young children can be improved by conjugating the polysaccha...
<ul><li>In general the Pneumococcal vaccine should be given to Children having </li></ul><ul><ul><li>heart condition  </li...
Infants under one year of age:   Give PCV vaccine as routinely recommended at two and four months of age with a booster do...
Don’t give the  PCV   vaccine to   Children  had a serious (life-threatening) allergic reaction to a previous dose of this...
<ul><li>Adverse effects following PCV   </li></ul><ul><li>25% had local  redness, tenderness, or swelling </li></ul><ul><l...
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Haemoglobinopathies

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Transcript of "Haemoglobinopathies"

  1. 1. By Prof. Dr. Asmaa AbdulAziz
  2. 2. Definition: The haemoglobinopathies are inherited disorders of haemoglobin synthesis (thalassaemias) or structure (sickle cell disorders) that are responsible for significant morbidity and mortality allover the world. They are seen mainly in individuals who originate from Africa, the Middle East,, the Mediterranean, Asia and the Far East. However, the increased mobility of the world’s population and inter-ethnic mixing lead to prevailing of these conditions within any region of the world.
  3. 3. These disorders result in errors in oxygen-carrying capacity of haemoglobin . Diseases linked to genetic predisposition are not only kill prematurely, but result in long years of ill health and disability, loss of work and income, possible poverty, loneliness and depression .
  4. 4. Sickle cell and thalassaemia are inherited disorders that are passed on from parents to children through unusual haemoglobin genes. People only have these disorders if they inherit two unusual haemoglobin genes – one from their mother, and one from their father. People who inherit just one unusual gene are known as ‘carriers’. (Some people call this having a ‘trait’.) Carriers are healthy and do not have the disorders.
  5. 5. <ul><li>Individuals with Haemoglobinopathy are: </li></ul><ul><ul><ul><li>either healthy carriers ( trait ) i.e. unaware of their carrier status unless specifically screened. If a couple both carry a haemoglobinopathy trait there is a 1 in 4 chance with each pregnancy that their child will inherit a clinically manifested haemoglobinopathy. </li></ul></ul></ul><ul><ul><ul><li>or having clinically manifested haemoglobinopathy </li></ul></ul></ul>
  6. 6. Who can be a carrier? Anyone can be a healthy carrier. This means you are more likely to be a carrier if your ancestors came from the Mediterranean (for example Cyprus, Italy, Portugal, Spain), Africa, the Middle East, India, Pakistan, South America or south and south-east Asia. Is it important to know if you are a carrier? 1- Healthy sickle cell carry may have some problems in rare situations (Lack of oxygen ,for example), when having an anesthetic or during deep-sea diving. Knowing that you carry sickle cell can help you manage these situations. However, people who carry thalassaemia or other unusual haemoglobin genes do not experience these problems. 2-If a carrier gets married from another carrier (Consanguinity) they will have one in four baby with clinically manifested disorders
  7. 7. The diagram below shows the chances (for each pregnancy) of two carrier parents having a child with a sickle cell or thalassaemia disorder.
  8. 8. If the mother is anemic & the father is healthy carrier 50% of the off springs are carriers and 50% is anaemic
  9. 9. Sickle Cell is a condition that affects the normal oxygen carrying capacity of red blood cells. When the cells are de-oxygenated and under stress in sickle cell conditions, they can change from round flexible disc-like cells to elongated sickle or crescent moon shape. The effect of these changes is that the cells do not pass freely through small capillaries and form clusters, which block the blood vessels. This blockage prevents oxygenation of the tissues in the affected areas resulting in tissue hypoxia and consequent pain (known as sickle cell crisis pain ) other symptoms of sickle cell disorders include severe anaemia, susceptibility to infections and damage to major organs.
  10. 10. The term sickle-cell disease is preferred because it is more comprehensive than sickle-cell anaemia.
  11. 13. 2-The clinically significant haemoglobinopathies are listed in following Table
  12. 14. <ul><li>In children, sickle-shaped red blood cells often become trapped in the spleen, leading to a serious risk of death before the age of seven years from a sudden profound anaemia associated with rapid splenic enlargement or because lack of splenic function permits an infection. </li></ul><ul><li>Affected children may present with painful swelling of the hands and/or feet (hand-foot syndrome). </li></ul><ul><li>Survivors may suffer recurrent & severe painful crises , as well as “ acute chest syndrome” (pneumonia or pulmonary infarction), bone or joint necrosis, or renal failure. </li></ul>
  13. 15. Thalassaemia Major : It is the most severe form of thalassaemia, results in the inability of the body to produce haemoglobin, resulting in life threatening anaemia. Those with the condition require regular therapeutic treatment and blood transfusion . Bone marrow transplantation is a treatment option
  14. 16. The impacts of genetic disorders on infectious diseases (Malaria & Sickle cell disorders) Many studies showed reduced morbidity and mortality from malaria ( Falciparum ) patients with thalassemia major and minor (the carriers) (up to 50%), and decreased numbers of circulating parasites (by 80%) The mechanism of resistance may consist of decreased parasite replication within the erythrocyte or enhanced splenic clearance of parasitized erythrocytes . A person who carries the sickle cell gene has a survival advantage against malaria
  15. 17. <ul><li>The sickle cell trait confers a selective advantage: resistance to severe malaria . The mechanism of this protection however, remains incompletely understood. Proposed mechanisms include </li></ul><ul><ul><ul><li>decreased parasite growth in the red cells and </li></ul></ul></ul><ul><ul><ul><li>enhanced removal of parasitized cells by the spleen. </li></ul></ul></ul><ul><li>In patients with sickle cell trait, although some protection against malaria and its complications is present, severe or complicated malaria can occur. </li></ul><ul><li>However , severe hemolytic & infarctive crises are anticipated if patients with sickle cell diseases get Malaria </li></ul>
  16. 18. Prevalence of haemoglobinopathies   The World Health Organization (WHO) estimates that globally at least : approximately 5% of adults are carriers for a haemoglobin condition 2.9% for thalassaemia and 2.3% for sickle cell diseases Carriers are found allover the word because as a result of migration the populations of different ethnic groups to different regions of the world.
  17. 20. Prevalence of Sickle cell disorders
  18. 22. SITUATION in Africa The highest prevalence of sickle-cell trait is in parts of Africa & among people with origins in equatorial Africa, the Mediterranean basin and Saudi Arabia. In Africa, the highest prevalence of sickle-cell trait occurs between latitudes 15° North and 20° South
  19. 23. Over 300 000 children are born each year with a severe haemoglobinopathy. 30% are born with thalassaemia syndromes while 70% have sickle-cell anaemia With worldwide migration, these diseases are as much a feature of Europe, the United States and Australia as of the countries where they originated. Prevalence varies from under 0.1 births per 1,000 in some parts of the world to more than 20 per 1,000 in parts of Africa . In America, approximately 70,000- 80,000 people suffer from sickle cell disease . They are mainly of African Origin       
  20. 25. The situation in KSA: In a study carried in KSA ,the incidence of hemoglobulin S for the studied neonates was 14.4% and ranged from 0.8% in Najran to 26.4% in Al-Qurayyat, KSA. In the eastern provinces the disease is generally milder whereas in the western provinces the disease is severe and similar to that reported in African populations
  21. 26. <ul><li>In Bahrain Genetic disorders of haemoglobin are prevalent. In a study of the hospital population covering </li></ul><ul><li>56 ,198 Bahrainis, it was found that </li></ul><ul><li>Sickle-cell disease was 2% of newborns </li></ul><ul><li>Sickle-cell trait was 18% of newborns </li></ul><ul><li>Carriers of the thalassaemia gene was 24% of newborns . </li></ul><ul><li>From this study it was concluded that </li></ul><ul><li>The mild form of SCD predominates. </li></ul><ul><li>Hematological values are similar to those of patients from Eastern Province, Saudi Arabia, where the mild form of the disease predominates </li></ul>
  22. 27. <ul><li>Sickle-cell disease in Bahrain and Saudi Arabia presents special features. SCD in this area is clinically mild, and mortality is low in both children and adults . </li></ul><ul><li>However, some cases died from septicemias & Pneumococcal diseases. </li></ul><ul><li>In this study the most precipitating factors for crisis were: </li></ul><ul><ul><ul><ul><ul><li>Exposure to cold (45% of cases). </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Fever or elevated body temperature (35%), </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Exhaustion & severe physical activity (35%), </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Hot humid weather (10%) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Crowded places (10%) </li></ul></ul></ul></ul></ul>
  23. 28. National Control program for haemoglobinopathies: The development of appropriate national control programme is now accepted and introduced in many parts of Asia such as in Bahrain, the Islamic Republic of Iran and Saudi Arabia . China, India, Indonesia, Malaysia, Maldives, Singapore and Thailand.
  24. 29. <ul><li>The control program depends on the characteristics & the requirements of individuals with haemoglobinopathies. </li></ul><ul><li>Sickle cell disorders :People with sickle cell disorders: </li></ul><ul><ul><li>• can have attacks of very severe pain </li></ul></ul><ul><ul><li>• can get serious, life-threatening infections </li></ul></ul><ul><ul><li>• are usually anaemic </li></ul></ul><ul><ul><li>• need medicines (antibiotics & Pneumococcal vaccine) throughout their lives to prevent infections. </li></ul></ul><ul><li>Thalassaemia major People with thalassaemia major: </li></ul><ul><ul><li>• are very anaemic </li></ul></ul><ul><ul><li>• need blood transfusions every four to six weeks, </li></ul></ul><ul><ul><li>• need injections and medicines throughout their lives. </li></ul></ul><ul><ul><li>There are also other, less common, haemoglobin disorders. Many of these are not serious . </li></ul></ul>
  25. 30. National Control program for sickle cell diseases 1- setting up sickle-cell screening and genetic counseling programmes in high prevalence countries. The disease should be identified during the prenatal period or at birth as part of a routine screening programme. Genetic counseling and screening can lead to reduction in the number of children born with the trait. The programme should be developed at the primary care level with appropriate referral system. 3-Parents must be counseled to seek medical care for all febrile events in children with sickle cell diseases. 2-Supplementation of antibiotics, rest, good nutrition, folic acid 3-Training of health personnel in prevention, diagnosis and case management should be an integral part of the national programme. 4-Integration of national control program for sickle-cell disease within the national programmes for prevention & control of non-communicable diseases (Cancer , Diabetes)
  26. 31. <ul><li>The antenatal screening programme </li></ul><ul><li>Parent screening for sickle cell and thalassaemia aims to </li></ul><ul><li>identify women/couples at risk of a pregnancy with sickle cell or thalassaemia disorders and </li></ul><ul><li>provide appropriate referral & care for prenatal diagnosis with continuation or termination of pregnancy according to women’s choices. </li></ul><ul><li>In most of the countries where sickle-cell disease is a major public health concern: </li></ul><ul><ul><li>National programmes for its control do not exist. </li></ul></ul><ul><ul><li>Basic facilities to manage patients are absent, </li></ul></ul><ul><ul><li>Screening for sickle-cell disease is not common practice The diagnosis of the disease is made when severe complication occurs. </li></ul></ul><ul><li>As a result, more than 50% of the children with the severe form of the disease die before the age of five from infection or severe anaemia </li></ul>
  27. 32. ANTENATAL SCREENING Pregnancy Offer screening Blood sent to laboratory for haemoglobinopathy Screen Positive results Information & counseling-Offer partner screening Partner screening Blood sent to laboratory for haemoglobinopathy Screen Positive results: At risk couple Information & counseling-Offer prenatal diagnosis Affected fetus- Information &counseling Parents Make- Informed Choice Termination of Pregnancy Prenatal diagnosis Fetal blood Sampling/ Chorionic Villus sampling Negative Result Information: No further action Unaffected Fetus Information- No further action Negative Result Information: No further action Continue with Pregnancy
  28. 33. Premarital diagnosis : In the Saudi society, consanguineous marriages are high (60%). Recently, the Saudi government introduced a new legislation regarding premarital testing for the 2 common genetic disorders; namely, sickle cell trait and thalassemia. The advantage of premarital diagnosis is that : affected births could be prevented if couples at risk were identified.
  29. 34. <ul><li>NEONATAL SCREENING </li></ul><ul><li>The newborn sickle cell screening is part of the existing bloodspot programme for Phenylketonurea (PKU) and congenital hypothyroidism (CHT). </li></ul><ul><li>Neonatal haemoglobinopathy screening primarily aims to </li></ul><ul><li>identify infants with SCDs , in order to start prophylactic antibiotic therapy and vaccination ( Pneumococcal vaccine) as early as possible. </li></ul><ul><li>detects carriers. For each baby detected with SCDs, neonatal screening detects between 17 and 100 sickle cell carrier babies. Parents of a carrier child should be informed about the carrier result </li></ul>
  30. 35. <ul><li>In UAE, a standard form for neonatal screening is issued to every baby born hospital, where 99% of deliveries occur, and mothers are informed about the procedures &importance of neonatal screening. </li></ul><ul><li>in January 1995 by screening for Phenylketonurea. </li></ul><ul><li>in January 1998. Screening for congenital hypothyroidism </li></ul><ul><li>In January 2002, the Ministry of Health decided to launch a pilot study for neonatal screening of sickle cell disease before expanding it at the national level. </li></ul><ul><li>Newborn infants are brought to MCH centre on the fifth day for collection of blood samples by heel prick onto filter paper </li></ul><ul><li>The aim of the Screening program for haemoglobinopathy is to: </li></ul><ul><ul><li>To detect infants with haemoglobin traits, </li></ul></ul><ul><ul><li>To identify children with clinical disease and </li></ul></ul><ul><ul><li>To counsel couples at risk for having future baby with sickle cell disorders. </li></ul></ul><ul><li>All infants confirmed with sickle cell disease started prophylactic penicillin by the age of 2 months and follow-up was arranged with the cooperation of haematologist. </li></ul>
  31. 36. <ul><li>Genetic counseling </li></ul><ul><li>It is the process through which knowledge about the genetic aspects of illnesses is shared by trained professionals with those who are at an increased risk or either having a genetic disorders or having them to be passed to their unborn offspring. </li></ul><ul><li>Genetic counseling is aiming to </li></ul><ul><ul><li>replace misunderstandings of the causes of genetic disease with correct information </li></ul></ul><ul><ul><li>informing parents about the resources available for diagnosis, treatment and prevention. </li></ul></ul><ul><ul><li>helping the families in decision making, which have life long consequences </li></ul></ul><ul><li>The family physician usually handles most of the genetic counseling during routine clinical visits </li></ul>
  32. 37. A survey of 500 parents, with children who have a genetic diseases was carried, to find their knowledge about genetic diseases indicated that the majorities were unaware of etiologies, symptoms, inheritance and therapies. This was particularly true for parents with lower education. Until recently a genetic counselor only advised of possibilities of recurrence of such a disease in the family. The new policy of genetic counseling is to help the family in making the correct decision for preventing the disease in the extended family and the prevention of a similar condition in future pregnancies .
  33. 38. <ul><li>Pneumococcal diseases in children with Sickle cell disorders : </li></ul><ul><li>Children with sickle cell anaemia have an increased susceptibility to severe bacteria infection, particularly from Streptococcus pneumoniae . The risk of infection is greater in the first 3 years of life specially at4 months. </li></ul><ul><li>The incidence of Pneumococcal diseases for children with sickle cell disease is 18.4cases per 100 patients/year compared with 0.02 to 0.06 patientss per 100 healthy children /year </li></ul><ul><li>This infection may be the first clinical manifestation of disease and carries . </li></ul><ul><li>The case fatality rate of Pneumococcal diseases in these children is 30% </li></ul>
  34. 39. Age distribution of pneumococcal bacteremia in children with sickle cell disease or HIV and healthy children at Boston Medical Center, 1981–1998 .9
  35. 40. <ul><li>Pneumococcal diseases in sickle cell children include </li></ul><ul><li>Pneumonia & bronchitis </li></ul><ul><li>Pneumococcal meningitis </li></ul><ul><li>Septicemias </li></ul><ul><li>Ear infections </li></ul><ul><li>Peritonitis </li></ul>
  36. 41. <ul><li>The Risk Factors for Recurrent Pneumonia in Children which include : </li></ul><ul><ul><li>Sickle-cell diseases </li></ul></ul><ul><ul><li>Impaired immune system ) HIV, cancer, leukemia ( </li></ul></ul><ul><ul><li>Viral respiratory Infections </li></ul></ul><ul><ul><li>Gastroesophageal reflux disorder </li></ul></ul><ul><ul><li>Inborn lung or heart defects </li></ul></ul><ul><ul><li>Asthma </li></ul></ul>
  37. 42. <ul><li>The causative agents : Streptococcus pneumonia </li></ul><ul><li>Children under 2 years old are at highest risk for serious disease. </li></ul><ul><li>The organisms spread from person to person through close contact. </li></ul><ul><li>Pneumococcal infections can be hard to treat because the bacteria have become resistant to some of the drugs that have been used to treat them. This makes prevention of Pneumococcal infections is more important. </li></ul>
  38. 43. Pneumococcal vaccine can help prevent serious Pneumococcal disease, such as pneumonia, bronchitis meningitis and septicemia & ear infections.
  39. 44. There are two types of Pneumococcal vaccine: 1- Pneumococcal polysaccharide vaccine (PPV) contains purified capsular polysaccharide from each of 23 serotypes of Pneumococcal bacteria 2-Pneumococcal conjugate vaccine (PCV) contains capsular polysaccharide from seven serotypes of Pneumococcal bacteria conjugated to protein The vaccines are inactivated, do not contain live organisms and cannot cause the diseases against which they protect.
  40. 45. <ul><li>Pneumococcal polysaccharide vaccine (PPV) </li></ul><ul><li>Adults develop a good antibody response to a single dose of PPV by the third week following immunization. </li></ul><ul><li>Not used in children < two years of age because of poor antibody responses . </li></ul><ul><li>The overall efficacy in preventing Pneumococcal bacteraemia is 50 to 70% </li></ul><ul><li>Post-immunization antibody levels begin to wane after five years </li></ul>
  41. 46. Pneumococcal conjugate vaccine (PCV) The antibody response in young children can be improved by conjugating the polysaccharide to proteins. The conjugated vaccine is immunogenic in children . The efficacy is 97% after giving the fourth dose The vaccine protects against Pneumococcal meningitis, bacteraemia, pneumonia and otitis media. For children under one year of age: ) First dose of 0.5ml of PCV at 2 nd month Second dose of 0.5ml, at 4 th month A third dose of 0.5ml at 6 th month The fourth dose of 0.5ml at 13 th month Subcutaneous at anterolateral thigh Children over one year of age and under five years of age: A single dose of 0.5ml of PCV (subcutaneous upper arm)
  42. 47. <ul><li>In general the Pneumococcal vaccine should be given to Children having </li></ul><ul><ul><li>heart condition </li></ul></ul><ul><ul><li>chronic lung ,liver disease </li></ul></ul><ul><ul><li>diabetes mellitus </li></ul></ul><ul><ul><li>weakened immune system </li></ul></ul><ul><ul><li>Children with damaged spleen or no spleen Or Sickle cell anaemia & thalassaemias . </li></ul></ul><ul><ul><li>These children should be managed as follow: </li></ul></ul>
  43. 48. Infants under one year of age: Give PCV vaccine as routinely recommended at two and four months of age with a booster dose at around 13 months of age. Children aged 12 months to < five years If they have a single dose of PCV before ,they should receive a second dose of PCV ( Separated by two months) because they may have a reduced immune response for the first dose of the vaccine. At-risk children aged five years and over PCV is not recommended .
  44. 49. Don’t give the PCV vaccine to Children had a serious (life-threatening) allergic reaction to a previous dose of this vaccine ( as it contains protein) Give the PCV vaccine to Children even with minor illnesses, such as mild fever or diarrhea Postponed the PCV vaccine for children who are moderately or severely ill .Wait until they recover before getting the vaccine
  45. 50. <ul><li>Adverse effects following PCV </li></ul><ul><li>25% had local redness, tenderness, or swelling </li></ul><ul><li>• Up to about 1 out of 3 had a fever </li></ul><ul><li>• Some children become drowsy, or had anorexia </li></ul><ul><li>So far, no serious reactions have been associated with this vaccine. </li></ul>
  46. 51. Best Wishes
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