Sickle Cell Disease In Pregnancy
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Sickle Cell Disease in pregnancy BY DR. JAMES E. OMIETIMI Department Of Obstetrics & Gynaecology University Of Port Harcourt Teaching Hospital Port Harcourt
Introduction Normal haemoglobin Type of normal haemoglobin molecule in normal human adult Abnormal haemoglobin Mutations of structural gene Genetically determined defects in the production rate of one or more of the globin chain Effect of HbSS on pregnancy Effect of pregnancy on HbSS Management of pregnancy in HbSS
Introduction:
Sickle cell syndromes are the most widespread of all genetic disorders. The disease manifest as chronic haemolytic anaemia, painful vaso-occlusive crises of varying severity and organ damage due to repeated episodes of micro-infarction.
Sickle cell disease was first reported by Herrick in 1910: (he reported finding sickle-shaped red blood cells in the blood film of a West Indian student who had cardiac murmur and severe anaemia.
NORMAL HAEMOGLOBIN
The normal human haemoglobin comprises four globin chains attached to a common haem group. The globin chains are polypeptide chains (2 pairs of unlike polypeptide chains attached to a common haem moiety). The physiological functioning of the haemoglobin molecule is dependent on the integrity of the haem moiety as well as the amino acid sequence and conformation of the globin chains.
TYPES OF HAEMOGLOBIN MOLECULES IN A NORMAL HUMAN ADULT
(Types of globin chains) HbA – α2 β2 chains (95% of total haemoglobin in adult)
HbA2 –α2∂2 chains (2 - 3.5%) HbF – α2 γ2 chains (< 2%) Note: HbA2 constitute < 5% of total haemoglobin at 1 year of life. The alpha chains consist of 141 amino acid residues and it is common to all 3 types of haemoglobin molecules, while the beta, delta and gamma chains each have 146 amino acid residues.
ABNORMAL HAEMOGLOBINS
They result from (i) mutations of a structural gene and (ii) genetically determined defects in the rate of production of one or more of the globin chains.
MUTATIONS OF STRUCTURAL GENES:
A separate autosomal genetic locus determines the primary structure of each of the four types of globin chains. Normally a person has 2 alleles at each locus – one inherited from each parent. A point mutation occurs at codon 6 of the beta-globin gene (an A for T substitution at codon 6 of the DNA) resulting in a single base change. This leads to the insertion of an incorrect amino acid in the globin chains.
In haemoglobin S (HbS) – the glutamic acid in the 6th position of the beta chain is replaced by valine – this results in a net gain of one positive charge and hence a different electrophoretic mobility to haemoglobin A on electrophoresis. Haemoglobin C (HbC) – the glutamic acid residue in the 6th position of the beta chain is replaced by lysine. HbC is most common in West Africa (highest incidence in Ghana) Haemoglobin E (HbE) – it is the second most common haemoglobin variant worldwide, it results from a single beta chain substitution of lysine for glutamic acid residue at codon 26.
GENETICALLY DETERMINED DEFECTS IN THE PRODUCTION RATE OF ONE OR MORE OF THE GLOBIN CHAINS – THALASSAEMIA:
TYPES OF THALASSAEMIA alpha Thalassaemia (minor and major) beta Thalassaemia (minor and major)
ALPHA THALASSAEMIA
– results from defect in the synthesis of the alpha globin chain. Alpha Thalassaemia major – results from complete deletions of all 4 alpha globin chain genes. There is complete absence of alpha globin chain synthesis. The fetus is affected because HbF is not produced. The absence of alpha globin chain results in production of haemoglobin Bart (4 gamma globin chains) and haemoglobin H (4 beta globin chains) as abnormal tetramers. Haemoglobin Bart has an appreciably increased affinity to oxygen, the fetus usually dies inutero or immediately after delivery – demonstrates typical clinical features of non-immune hydrops fetalis (fetal ascites following intrauterine cardiac failure, large placenta), Hb Bart is a common cause of stillbirth in Southeast Asia.
Haemoglobin H disease – results from deletions of 3 of the 4 alpha globin chain genes. This is compatible with extrauterine life. The abnormal red cells at birth contain a mixture of Hb Bart, HbH and HbA. The neonate appears well at birth, but after early infancy, hemolytic anaemia develops. Most of the 20-40% Hb Bart at birh is replaced later by HbH. In adults, HbH constitute 5-30% of their haemoglobin. The disease is characterized by anaemia of varying severity and the anaemia worsens during pregnancy in such women.
Alpha Thalassaemia minor
– results from deletions of 2 of the 4 alpha globin chain genes. It is characterized by minimal to moderate hypochromic microcytic anaemia. There is no associated clinical abnormality, hence it often goes unrecognised. Hb Bart is present at birth, but it is not replaced by HbH in later life. The red blood cells are hypochromic and microcytic. The haemoglobin concentration varies between normal to slightly depressed. Women with alpha Thalassaemia minor appear to tolerate pregnancy quite well.
Silent carrier state – results from single gene deletion of the 4 alpha globin chain genes. No clinical abnormality is evident in these individuals. Incidence – alpha thalassaemia minor, Hb Bart and HbH disease are common in Asia. Alpha thalassaemia minor occurs in 2% of African, HbH is extremely rare, while Hb Bart is unreported.
BETA THALASSAEMIA
– results from defect in the synthesis of beta globin chain. Beta thalassaemia major (Cooley’s anaemia) – excess of alpha globin chain precipitates resulting in red cell membrane damage. The neonate is normal at birth, but as HbF level falls, the infant becomes severely anaemic and fails to thrive.
If they are entered into an adequate transfusion programme, they develop normally until the 1st decade of life, when the effect of iron overload becomes apparent, but prognosis is improved with iron-chelation therapy. Females who survive beyond childhood usually are sterile. Life expectancy even with transfusion therapy is short. Pregnancy is rare, but successful outcomes have been reported.
Beta thalassaemia minor
– percentage of HbA2 in the adult is higher than 3.5%, while that of HbF is > 2%. The red cells are hypochromic and microcytic, but anaemia is mild. The haemoglobin concentration is typically 8-10g/dl in late second trimester, rising to 9-11g/dl near term compared to haemoglobin concentration of 1012g/dl in the non-
There is usually pregnancy-induced erythropoiesis with resultant normal blood volume expansion and a slightly subnormal red cell mass expansion. Women with beta thalassaemia minor do not require any specific therapy during pregnancy – maternal and fetal outcome usually is satisfactory. Daily prophylactic iron and
Some abnormal haemoglobin variants produce clinical manifestations only in the homozygous state (e.g. HbSS) or when combined with a second haemoglobin variant (e.g. HbSC). The major complication of sickle cell disease is anaemia and intravascular thrombosis. In the oxygenated state, the solubility of HbS is nearly equal to that of HbA. However, in the deoxygenated state;
A significant increase in blood viscosity is produced by a level of sickling greater than 15%. If the total HbS can be reduced to less than 20% of total haemoglobin (i.e. 80% HbA), blood viscosity will not increase except in states of severe deoxygenation, and this provides the basis for prophylactic blood transfusion therapy. In sickle cell disease, where 75-100% of the total haemoglobin in the rell cell is HbS, crises may occur when oxygen tension is only slightly
The kidneys with its hypertonic milieu in the medulla present an opportunity for sickling even at a relatively high oxygen tension – the microinfarctions result in peritubular haemorrhage, interstitial scarring and an increased susceptibility to pyelonephritis (UTI). HbSS are prone to respiratory infection – pneumonia, skeletal complications resulting from erythroid hyperplasia (very marked) may produce osteoporosis and pathological fractures, bone infarction (aseptic necrosis of femur head), this could lead to fat and marrow embolism. Crises may result following infections, dehydration, extreme of heat or cold, or stress. The treatment of a painful crisis should include careful search for and treatment of the precipitating cause as well as general supportive measures such bed rest, analgesia, warmth, rehydration and oxygen therapy. Haemolytic crises is diagnosed following sudden drop in blood count and rise in reticulocyte count
HbC does not in itself sickle. HbC and HbD moves with HbS on electrophoresis in alkaline buffers but which do not themselves sickle. Sickle cell disease is a sickling disorder in which the sickle gene is present with another abnormal gene affecting either the production or structure of haemoglobin (i.e. HbSC, HbSThal) Sickle cell anaemia is HbSS Sickle cell trait is HbAS - prone to UTI in pregnancy, do not normally suffer from sickling crises and the presence of the S haemoglobin confers partial protection from Plasmodium falciparum malaria. Patient with HbSC and HbSThal may not be aware of their haemoglobinopathy status, because they usually have very few crises. However, those with HbSS usually know their status because of repeated crises.
EFFECT OF HbSS ON PREGNANCY
Increased incidence of spontaneous abortion. Increased incidence of stillbirth. Preterm delivery Neonatal death Intrauterine growth retardation Increased maternal morbidity and mortality Increased incidence of pre-eclampsia and eclampsia Increased susceptibility to infections –
EFFECT OF PREGNANCY ON HbSS
Increase frequency of crises Worsening of anaemia.
Introduction Normal haemoglobin Type of normal haemoglobin molecule in normal human adult Abnormal haemoglobin Mutations of structural gene Genetically determined defects in the production rate of one or more of the globin chain Effect of HbSS on pregnancy Effect of pregnancy on HbSS Management of pregnancy in HbSS
Introduction:
Sickle cell syndromes are the most widespread of all genetic disorders. The disease manifest as chronic haemolytic anaemia, painful vaso-occlusive crises of varying severity and organ damage due to repeated episodes of micro-infarction.
Sickle cell disease was first reported by Herrick in 1910: (he reported finding sickle-shaped red blood cells in the blood film of a West Indian student who had cardiac murmur and severe anaemia.
NORMAL HAEMOGLOBIN
The normal human haemoglobin comprises four globin chains attached to a common haem group. The globin chains are polypeptide chains (2 pairs of unlike polypeptide chains attached to a common haem moiety). The physiological functioning of the haemoglobin molecule is dependent on the integrity of the haem moiety as well as the amino acid sequence and conformation of the globin chains.
TYPES OF HAEMOGLOBIN MOLECULES IN A NORMAL HUMAN ADULT
(Types of globin chains) HbA – α2 β2 chains (95% of total haemoglobin in adult)
HbA2 –α2∂2 chains (2 - 3.5%) HbF – α2 γ2 chains (< 2%) Note: HbA2 constitute < 5% of total haemoglobin at 1 year of life. The alpha chains consist of 141 amino acid residues and it is common to all 3 types of haemoglobin molecules, while the beta, delta and gamma chains each have 146 amino acid residues.
ABNORMAL HAEMOGLOBINS
They result from (i) mutations of a structural gene and (ii) genetically determined defects in the rate of production of one or more of the globin chains.
MUTATIONS OF STRUCTURAL GENES:
A separate autosomal genetic locus determines the primary structure of each of the four types of globin chains. Normally a person has 2 alleles at each locus – one inherited from each parent. A point mutation occurs at codon 6 of the beta-globin gene (an A for T substitution at codon 6 of the DNA) resulting in a single base change. This leads to the insertion of an incorrect amino acid in the globin chains.
In haemoglobin S (HbS) – the glutamic acid in the 6th position of the beta chain is replaced by valine – this results in a net gain of one positive charge and hence a different electrophoretic mobility to haemoglobin A on electrophoresis. Haemoglobin C (HbC) – the glutamic acid residue in the 6th position of the beta chain is replaced by lysine. HbC is most common in West Africa (highest incidence in Ghana) Haemoglobin E (HbE) – it is the second most common haemoglobin variant worldwide, it results from a single beta chain substitution of lysine for glutamic acid residue at codon 26.
GENETICALLY DETERMINED DEFECTS IN THE PRODUCTION RATE OF ONE OR MORE OF THE GLOBIN CHAINS – THALASSAEMIA:
TYPES OF THALASSAEMIA alpha Thalassaemia (minor and major) beta Thalassaemia (minor and major)
ALPHA THALASSAEMIA
– results from defect in the synthesis of the alpha globin chain. Alpha Thalassaemia major – results from complete deletions of all 4 alpha globin chain genes. There is complete absence of alpha globin chain synthesis. The fetus is affected because HbF is not produced. The absence of alpha globin chain results in production of haemoglobin Bart (4 gamma globin chains) and haemoglobin H (4 beta globin chains) as abnormal tetramers. Haemoglobin Bart has an appreciably increased affinity to oxygen, the fetus usually dies inutero or immediately after delivery – demonstrates typical clinical features of non-immune hydrops fetalis (fetal ascites following intrauterine cardiac failure, large placenta), Hb Bart is a common cause of stillbirth in Southeast Asia.
Haemoglobin H disease – results from deletions of 3 of the 4 alpha globin chain genes. This is compatible with extrauterine life. The abnormal red cells at birth contain a mixture of Hb Bart, HbH and HbA. The neonate appears well at birth, but after early infancy, hemolytic anaemia develops. Most of the 20-40% Hb Bart at birh is replaced later by HbH. In adults, HbH constitute 5-30% of their haemoglobin. The disease is characterized by anaemia of varying severity and the anaemia worsens during pregnancy in such women.
Alpha Thalassaemia minor
– results from deletions of 2 of the 4 alpha globin chain genes. It is characterized by minimal to moderate hypochromic microcytic anaemia. There is no associated clinical abnormality, hence it often goes unrecognised. Hb Bart is present at birth, but it is not replaced by HbH in later life. The red blood cells are hypochromic and microcytic. The haemoglobin concentration varies between normal to slightly depressed. Women with alpha Thalassaemia minor appear to tolerate pregnancy quite well.
Silent carrier state – results from single gene deletion of the 4 alpha globin chain genes. No clinical abnormality is evident in these individuals. Incidence – alpha thalassaemia minor, Hb Bart and HbH disease are common in Asia. Alpha thalassaemia minor occurs in 2% of African, HbH is extremely rare, while Hb Bart is unreported.
BETA THALASSAEMIA
– results from defect in the synthesis of beta globin chain. Beta thalassaemia major (Cooley’s anaemia) – excess of alpha globin chain precipitates resulting in red cell membrane damage. The neonate is normal at birth, but as HbF level falls, the infant becomes severely anaemic and fails to thrive.
If they are entered into an adequate transfusion programme, they develop normally until the 1st decade of life, when the effect of iron overload becomes apparent, but prognosis is improved with iron-chelation therapy. Females who survive beyond childhood usually are sterile. Life expectancy even with transfusion therapy is short. Pregnancy is rare, but successful outcomes have been reported.
Beta thalassaemia minor
– percentage of HbA2 in the adult is higher than 3.5%, while that of HbF is > 2%. The red cells are hypochromic and microcytic, but anaemia is mild. The haemoglobin concentration is typically 8-10g/dl in late second trimester, rising to 9-11g/dl near term compared to haemoglobin concentration of 1012g/dl in the non-
There is usually pregnancy-induced erythropoiesis with resultant normal blood volume expansion and a slightly subnormal red cell mass expansion. Women with beta thalassaemia minor do not require any specific therapy during pregnancy – maternal and fetal outcome usually is satisfactory. Daily prophylactic iron and
Some abnormal haemoglobin variants produce clinical manifestations only in the homozygous state (e.g. HbSS) or when combined with a second haemoglobin variant (e.g. HbSC). The major complication of sickle cell disease is anaemia and intravascular thrombosis. In the oxygenated state, the solubility of HbS is nearly equal to that of HbA. However, in the deoxygenated state;
A significant increase in blood viscosity is produced by a level of sickling greater than 15%. If the total HbS can be reduced to less than 20% of total haemoglobin (i.e. 80% HbA), blood viscosity will not increase except in states of severe deoxygenation, and this provides the basis for prophylactic blood transfusion therapy. In sickle cell disease, where 75-100% of the total haemoglobin in the rell cell is HbS, crises may occur when oxygen tension is only slightly
The kidneys with its hypertonic milieu in the medulla present an opportunity for sickling even at a relatively high oxygen tension – the microinfarctions result in peritubular haemorrhage, interstitial scarring and an increased susceptibility to pyelonephritis (UTI). HbSS are prone to respiratory infection – pneumonia, skeletal complications resulting from erythroid hyperplasia (very marked) may produce osteoporosis and pathological fractures, bone infarction (aseptic necrosis of femur head), this could lead to fat and marrow embolism. Crises may result following infections, dehydration, extreme of heat or cold, or stress. The treatment of a painful crisis should include careful search for and treatment of the precipitating cause as well as general supportive measures such bed rest, analgesia, warmth, rehydration and oxygen therapy. Haemolytic crises is diagnosed following sudden drop in blood count and rise in reticulocyte count
HbC does not in itself sickle. HbC and HbD moves with HbS on electrophoresis in alkaline buffers but which do not themselves sickle. Sickle cell disease is a sickling disorder in which the sickle gene is present with another abnormal gene affecting either the production or structure of haemoglobin (i.e. HbSC, HbSThal) Sickle cell anaemia is HbSS Sickle cell trait is HbAS - prone to UTI in pregnancy, do not normally suffer from sickling crises and the presence of the S haemoglobin confers partial protection from Plasmodium falciparum malaria. Patient with HbSC and HbSThal may not be aware of their haemoglobinopathy status, because they usually have very few crises. However, those with HbSS usually know their status because of repeated crises.
EFFECT OF HbSS ON PREGNANCY
Increased incidence of spontaneous abortion. Increased incidence of stillbirth. Preterm delivery Neonatal death Intrauterine growth retardation Increased maternal morbidity and mortality Increased incidence of pre-eclampsia and eclampsia Increased susceptibility to infections –
EFFECT OF PREGNANCY ON HbSS
Increase frequency of crises Worsening of anaemia.
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