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 in-
utero 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 un-
reported.
 BETA THALASSAEMIA
 – results from defect  If they are entered into an
in the synthesis of
beta globin chain.
 Beta thalassaemia
major (Cooley’s
anaemia) – excess of
alpha globin chain
precipitates resulting
in red cell membrane
 Females who survive
damage.
 The neonate is normal
at birth, but as HbF
level falls, the infant
becomes severely
anaemic and fails to
thrive.
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.
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  There is usually
the adult is higher than pregnancy-induced
3.5%, while that of HbF erythropoiesis with
is > 2%. resultant normal blood
volume expansion and
 The red cells are a slightly subnormal
hypochromic and red cell mass
microcytic, but anaemia expansion. Women
is mild. with beta
 The haemoglobin thalassaemia minor do
concentration is not require any
typically 8-10g/dl in late specific therapy
second trimester, rising during pregnancy –
to 9-11g/dl near term maternal and fetal
compared to outcome usually is
haemoglobin satisfactory. Daily
concentration of 10- prophylactic iron and
12g/dl in the non-
 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.