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Pregnancy
Dr. P. Manjula Gunaratne
MBBS(Colombo), MRCOG(UK)
Physiology
Erythrocytes (Red Blood Cells)
Haemoglobin (Hb)
Erythrocytes (RBC)
Carry Hb in the circulation
Biconcave discs. 7.5um diameter, 2um thick
In mammals they loose their nuclei before
entering the circulation
In humans they survive for 120 days
Each contain 29pg of Hb
Normal count
Male 5.4million/ul
Female 4.8million/ul
Haemoglobin
Molecular weight 64,450
Globular molecule made up of 4
subunits
Each subunit contains a heme moiety
conjugated to a polypeptide (globin
chain)
Heme is iron containing porphyrin
derivative
There are 2 pairs of polypeptides in
each Hb molecule
chain 141 amino acids
chain 146 amino acids
( chain and cain also contain 146 aa)
Types of Haemoglobin in adult
Haemoglobin A 2 2 - normal adult Hb
Haemoglobin A2 2 2 - 2.5% of Hb
Oxygen attaching to Fe2+ in the heme
to form oxyhaemoglobin
Fetal Haemoglobin HbF is 2 2
Synthesis & Catabolism
of Hb
Red cells are synthesized in the bone marrow
They are destroyed in reticuloendothelial
system mainly spleen, tissue macrophages
Globin portion split of
Heme is converted to biliverdin and they
converted to bilirubin and excreted in bile
The iron in the heme is reused for Hb
synthesis
Classification of Anaemia
Physiological Anaemia
Acquired Anaemia
Nutritional
Iron deficiency
Folate deficiency
TB
Hereditary Anaemias
Thalassemias
Sickle cell haemoglobinopathies
Hereditary haemolytic anaemias
WHO Definition of Anaemia in
Pregnancy
Haemoglobin concentration
< 11g/dl at booking and
<10.5g/dl at 28 weeks
<10.0g/dl post partum
Classification of
anaemia
Class Haemoglobin
level
Mild 9-11
Moderate 7-9
Severe 4-7
Very severe <4
Effects on pregnancy
outcome
Increased risk of
Preterm delivery
Low birth weight
Prolonged labour
Placental abruption
Peripartum blood loss
Physiological Anaemia
During normal pregnancy there is increase in
Plasma volume by 40-50%
Red Cell Mass by 18-25%
These diferential changes cause dilution
decrease in Hb concentration
Starts at 7-8 weeks
This is maximal at 32 weeks gestation
Normal haematological changes in
pregnancy
Blood Changes
component during
pregnancy
Haemoglobin Decrease
(Hb)
Haematocrit Decrease
(PCV)
Red cell count Decrease Plasma volume
(RBC) increased at faster
Mean cell Increase
volume (MCV)
rate than Hb and RBC
Mean cell Hb No change are produced, leading
concentration to physiological
Serum iron & Decrease anaemia
Ferritin
Total iron Increase
Iron deficiency anaemia
Iron deficiency is the most common deficiency state in the world
afecting more than 2 billion people globally
Almost 50% of anaemia in pregnancy are due to iron deficiency
Iron deficiency represents a spectrum ranging from
Iron depletion - the amount of stored iron (serum ferritin) is reduced but
transport and functional iron may not be afected
Iron deficiency stored iron and transport iron ( transferrin saturation)
reduced
The amount of iron absorbed is not sufficient to replace the amount
lost
Shortage of iron limit red cell production and increased erythrocyte
protoporphyrin concentration
In iron deficiency anaemia there is shortage of iron stores, transport
and functional iron resulting reduced Hb in addition to low transferrin
saturation and increased erythrocyte protoporphyrin concentration
Physiology
In normal gestation the total iron requirement throughout
pregnancy is approximately 1g
300mg actively transported into fetus & placenta
200mg lost to various routes of excretion
500mg incorporated into increasing maternal Hb mass
Erythropoiesis increases progressively with gestational
age and returns to normal 5 weeks after delivery
There is uneven distribution of iron requirement during
pregnancy.
In the first trimester very low. 2.5mg/day due to
Absence of menstrual loss
Low Hb
Low MCV
Low MCH
Low MCHC
Blood Picture
Microcytic
hypochromic red
cells and
characteristic pencil
cells
Microcytic
hypochromic picture
also seen in
haemoglobinopathies
Serum Ferritin
Stable glycoprotein which accurately reflects iron stores in the absence of
inflammatory change
It is the first laboratory test to become abnormal as iron stores decrease
and it is not afected by recent iron ingestion
It is considered the best test to assess iron deficiency in pregnancy
It is an acute phase reactant and levels will rise when there is active
infection or inflammation or ingestion of alcohol
During pregnancy in women with adequate iron stores at conception the
serum ferritin concentration initially rises, followed by a progressive fall by
32 weeks to about 50% pre pregnancy levels. This is due to,
Haemodilution
Mobilisation of iron
The levels increase again mildly in the 3 rd trimester
Concentration < 15ug/l indicate iron depletion in all stages of pregnancy
Treatment should be considered when serum ferritin levels fall below
30ug/l
Concurrent measurement of CRP may be helpful in interpreting higher
levels
Serum Iron (Fe) & Total Iron Binding
Capacity (TIBC)
Serum Fe and TIBC are unreliable indicators
because of wide fluctuation in levels due to
Recent ingestion of Fe
Diurnal rhythm
Infection
Nutritional status
TIBC measures the affinity of the transport
protein (transferrin) to iron
Zinc protoporphyrin (ZPP)
Erythrocyte zinc protoporphyrin is the precursor of Heme
and increases in iron deficiency
ZPP increases when iron availability decreases as zinc
rather than iron is incorporated into protoporphyrin ring
Serum ZPP is not influenced by plasma dilution
Levels rise in the third trimester
It is afected by infection and inflammation less than
serum ferritin
RBC ZPP has greater sensitivity and specificity for iron
depletion but rarely performed
It is falsely elevated in inflammation, lead poisoning,
haemolytic anaemias
Soluble transferrin receptor (sTfR)
Sensitive measure of tissue iron supply
It is not an acute phase reactant
Transferrin receptor is a transmembrane protein which transport
iron into the cell
Circulating concentration of sTfR are proportional to cellular
expression of the membrane associated TfR and therefore give
accurate estimate of iron deficiency
There is little change in the early stages of iron depletion, but
once iron deficiency is established, the sTfR concentration
increases in direct proportion to total transferrin receptor
concentration
However this is an expensive test which restrict its general
availability and there is little data on its use in pregnancy
A value of 12mg/l or higher indicate iron deficiency anaemia
Reticulocyte haemoglobin content
and reticulocytes
Iron deficiency causes a reduction in
reticulocyte number and reticulocyte
haemoglobin concentration
This allow extremely early and objective
information
This is not widely available and there is no
data in pregnancy
Bone marrow iron
Bone marrow sample stained for iron is
considered gold standard for assessment of
iron stores
This is more invasive and not practical widely
But useful in most complicated cases in
pregnancy where underlying causes are not
identifiable by simple means
Trial of iron therapy
This is diagnostic and therapeutic
A trial of iron should be considered as the first
line diagnostic test for normocytic or microcytic
anaemia
Assessment of response to iron is both cost and
time efective
A rise in Hb should be demonstrable in 2 weeks
and confirms iron deficiency
Serum ferritin should be checked prior to starting
iron in patients with known haemoglobinopathy
Treatment of iron deficiency
anaemia
Dietary Advice
Oral iron
This is the treatment of choice if there is enough time ( maximum increase in
Hb is 0.8g/week
Intramuscular Iron
No longer recommended
Intravenous Iron
Numerous preparations exist- CosmoFe, Venofer is recommended in second &
third trimester
It is given as single dose infusion over 4-6 hours
Blood transfusion
Indicated
If woman is clinically unstable or
has significant bleeding or
Erythropoietin
Mainly used in iron deficiency anaemia associated with renal failure
Can be used in cases where blood transfusion has been declined Jehovahs
Witness
Dietary advice
In UK daily Fe intake is 10.5mg
Approximately 15% of dietary Fe is absorbed
Physiological iron requirement are 3 times higher in
pregnancy than in menstruating women
The recommended daily intake is 30mg in the latter half
of pregnancy
Absorption of iron increases 3 fold by third trimester, with
iron requirements increasing from 1-2mg to 6mg per day
The amount of iron absorption depends upon
the amount of iron in the diet
Its bioavailability
Physiological requirements
Dietary types of iron
Haem iron (15% of dietary iron)
Main sourses are haemoglobin & myoglobin from red meat, fish,
poultry
They are absorbed 2-3 fold more readily than non Haem iron
Heme iron may enhance absorption of non heame iron
Non haem iron (85% of dietary iron)
>95% of dietary iron intake are from non haem sourses
Vitamin C enhances iron absorption from non haem sourses
Germination and fermentation of cereals and legumes improve the
bioavailability of non haem iron by reducing the content of phytate
and enhance absorption
Tannnins in tea and cofee inhibit iron absorption when consumed
with meal or shortly after
Calcium, soy proteins, phytates,other inositol phosphates and
phenolic compounds inhibit absorption
Oral iron supplements
Oral iron is efective, cheap and safe way to replace iron
Ferrous salts show only marginal diferences between one another in
efficiency of absorption of iron
Ferric salts are much less well absorbed
Recommended dose of elemental iron for treatment of iron
deficiency is 100-200mg daily
Higher doses should not be given as absorption is saturated and
side efects increased
Available ferrous salts include
Ferrous fumarate (200mg iron compound = 66mg elemental iron)
Ferrous sulphate (300mg iron compound = 36mg elemental iron)
Ferrous gluconate (300mg iron compound = 36mg elemental iron)
Oral iron supplementation should be taken on an empty stomach
one hour before meals with a source of vitamin C (orange juice)as
absorption is afected by factors that afect non haem iron
Other medications or antacids should not be taken at the same time
Indications for oral iron
supplementation
Women with Hb <11g/dl up until 12 or <10.5g/dl
beyond 12 weeks should be ofered trial of iron
supplementation
In the presence of known haemoglobinopathy
serum ferritin should be checked and women
ofered therapeutic iron replacement if level is
<30ug/l
WHO, UNICEF and International Nutritional
Anaemia Consultative Group recommend a
single daily dose of 60mg elemental iron for 6
months during pregnancy
Response to oral iron
Hb concentration should rise by 2g/dl over 3-4 weeks (BNF 2010)
Compliance and intolerance of oral iron preparations can limit
efficacy
Up to 1/3rd of patients will develop dose limiting side efects
Gastric irritation
Nausea
Epigastric discomfort
Enteric coated or sustained release preparations should be avoided
as the majority of iron is carried past the duodenum limiting
absorption
The relationship between dose and altered bowel habits (diarrhoea &
constipation) is less clear. Laxatives may help
Repeat Hb in 2 weeks is required to assess response to treatment
Once Hb is in normal range treatment should be continued for
further 3 months and at least until 6 weeks post partum to replenish
iron stores
Postnatal anaemia
Postnatal anaemia is Hb <10g/dl (WHO)
FBC should be checked within 48 hours in all women
with
EBL >500ml
Women with uncorrected anaemia in antenatal period
Symptoms suggestive of postpartum anaemia
Women with Hb <10g/dl who are haemodynamically
stable, asymptomatic, or mildly symptomatic,
should be ofered elemental iron 100-200mg daily
for at least 3 months and repeat FBC and ferritin to
ensure Hb and iron stores are replete
Parenteral iron therapy
Indicated in
Absolute non compliance
Intolerance
Proven malabsorption
Parenteral iron therapy has
Faster increase in Hb
Better replenishment of iron stores
Better response particularly demonstrated for iron sucrose and iron
carboxymaltose
As free iron may lead to the production of hydroxyl radicals with potential
toxicity to tissues iron deficiency should be confirmed by ferritin levels
before use of parenteral iron
Contraindications
History of anaphylaxis
Reaction to parenteral iron therapy
First trimester of pregnancy
Active acute or chronic infection
Chronic liver disease
Intravenous iron preparations
Iron sucrose
Has higher availability for erythropoiesis than iron dextran
Total dose cannot be administered by single infusion but need multiple
infusions
Iron 111 carboxymaltose (Ferrinject)
A ferric hydroxide carbohydrate complex
A fast acting IV preparation
Allows controlled delivery of iron within the cells of reticuloendothelial
system (primarily bone marrow) and subsequent delivery to iron binding
proteins ferritin and transferrin
It is administered IV as single dose of 1000mg over 15 minutes
Maximum 15mg/kg by injection or 20mg/kg by infusion
Iron 111 isomaltose (Monofer)
Provide slow release of bioavailable iron to iron binding proteins
There is rapid uptake by reticuloendothelial system and little risk of release
of free iron
Doses >1000mg can be administered in a single infusion
Intramuscular
preparations
Low molecular weight iron dextran
Only IM preparation available in UK
Injections tend to be painful and there is a
significant risk of permanent skin staining
Its use is generally discouraged but if given the
Z track injection technique should be used to
minimise risk of iron leakage into the skin
Advantages & Disadvantages of oral &
parenteral iron
Parenteral Iron
Advantages Disadvantages
Oral Iron 100% compliance Invasive
Preferred in GIT Painful
Advantages Disadvantage malabsorption administration
s syndromes
No anaphylaxis GIT (ulcerative colitis,
crohns disease,
disturbances
tropical sprue)
Easy to take Metalic taste in Preferred in Staining and
mouth patients who are abscess
Cheap Non unable to tolerate formation at the
compliance oral iron peptic site of IM
ulcer disease injection site
Certainity of Anaphylaxis
restoration of reaction
stores in shorter
time span
Correction of Thromboplebhitis
anaemia near in IV site
Management of delivery
Consider
Delivery in hospital
IV access
Blood group & save
Active management of 3rd stage
Syntometrine or syntocinon IM
IV syntocinon infusion
Indications for and risk of blood
transfusion
Risks of blood transfusion
Clinical and laboratory errors
Transfusion induced sensitisation to red cell
antigens
The decision to transfuse post partum period
should be based on careful evaluation of
Risk of bleeding
Cardiac compromise
Symptoms requiring urgent attention
Folate deficiency
Causes megaloblastic anaemia
There is a clear link between periconceptual
folate deficiency and neural tube defects
Thus all women planning a pregnancy should
take 400ug/day till 12 weeks of pregnancy
High risk groups should take folic acid 5mg/day
Folate requirement also increases in pregnancy
due to
Increasing red cell mass
Expanding feto-placental unit
Folic Acid Metabolism
At cellular level
HbA2 levels
Increased in thalassaemias
Sickle cell disease
High performance liquid chromatography
(HPLC) anything other than HbAA is a variant
- thalassaemia
Those with trait can become anaemic during
pregnancy
Iron and folate supplementation should be given
although parenteral iron should be avoided
Maternal complications that occur when the
fetus has Hb Barts hydrops include
Severe pre eclampsia
Intrapartum problems secondary to delivery of
grossly hydropic fetus and placenta including
primary PPH
- thalassaemia
- thalassaemia minor (those with trait) are often
anaemic
They should take folic acid (5mg/day) and oral iron
supplementation if the ferritin level is low (never
parenteral iron)
If anaemia does not respond transfusion may be indicated
thalassaemia major
Pregnancy is possible with aggressive iron chelating
programmes and assisted conception
Iron overload can lead to
hepatic and endocrine dysfunction - (which lead infertility
secondary to pituitary failure)
Myocardial dysfunction look for cardiomyopathy
Management during
pregnancy
Manage jointly by obstetrician and haematologist
Assess (at the beginning)
Maternal iron status
Cardiology assessment
Partner screening for haemoglobinopathy
Treat
anaemia with blood transfusion
Folic acid 5mg/day
During pregnancy
Monitor fetal growth at regular intervals
Monitor maternal red cell antibody level
Fetal surveillance for anaemia by regular middle cerebral artery peak
systolic velocity
(history of regular transfusions means women often has multiple red cell
alloantibodies putting the fetus at risk of haemolytic disease of new
born)
Sickle Cell disease
Most common inherited disorder in UK and worldwide
Most prevalent in Africa and Caribbean
It is caused by sickle gene which afect Hb structure
Sickle cell disease include
Homozygous sickle cell disease (HBSS)
Heterozygous condition when HbS is co inhereted with
another abnormal Hb
HbC leading to HbSC
thalassaemia leading to HbS
Retinopathy
Leg ulcers
Cholelithiasis
Avascular necrosis
Haemophilus influenzae
Extrinsic causes
Red cell directed antibody autoimmune haemolytic anaemia
Altered intravascular circulation
DIC
Thrombotic thrombocytopenic purpura
Infection
Hereditary
spherocytosis
Autosomal dominant inheritance
Red cells are spherocytic and osmotically
fragile
The condition caused by defect in red cell
membrane proteins
Diagnosis
Non immune haemolysis
Blood film show spherocytes
Management
Monitor for anaemia
Folic acid 5mg/day supplementation
Aplastic crises can be caused by parvovirus
B19 infection
Treat with blood transfusion
Splenectomy ameliorate haemolytic anaemia
and gall stone formation
50% chance that child may be afected
Red cell metabolism
Disorders
Pyruvate kinase deficiency
Inherited as autosomal recessive fashion
Results varying degree of anaemia
G6PD deficiency
X- linked
Avoid oxidant stress, should take folic acid and
may need transfusion
Autoimmune haemolytic
anaemia
Due to
Drugs
Infection
Autoimmune disorders (SLE)
Neoplasia
Haematological disorders
Positive direct coombs test in the mainstay of diagnosis
Treat with
Glucocorticoids
Splenectomy
Immunosuppressive therapy azathioprin, cyclosporine,
cyclophosphamide
Aplastic Anaemia
Due to bone marrow failure leading to
pancytopenia
Causative agents
Infections
Medications
Toxins
Treatment
Supportive with blood products & growth factors
Bone marrow transplantation
Pregnancy may exacerbate bone marrow
depression and cause clinical deterioration
Diagnosis of Anaemia
Thank You
References
High risk pregnancy : anaemia & white blood
cell disorders : Jane Strong
UK guideline on the management of iron
deficiency in pregnancy : British Committee
for Standards in Haematology: July 2011