Hematological disorders in pregnancy

Report
Guide- Dr. Neeta Singh
CO-guide- Dr. Sujata Rawat
Candidate- Dr. Prerna
Headings
 Disorders of RBC’S –
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Anemia, Hemoglobinopathies & polycythemia
Disorders of WBC’s
Disorders of Platlets
Coagulation disorders – Inherited/Aquired
Hematological malignancies
Anemia
ANEMIAS OF DECREASED RBC
PRODUCTION
 DECREASED Hb
SYNTHESIS- MICROCYTIC
 IRON DEFICIENCY
 THALASSEMIA
 SIDEROBLASTIC ANEMIA
 DECREASED DNA
SYNTHESIS- Megaloblastic
anemia
 STEM CELL FAILURE –
Aplastic anemia
 ANEMIA OF CHRONIC
DISEASE
ANEMIA DUE TO RBC
DESTRUTION
 Hemolytic anemia
 Autoimmune
 Hemoglobinopathies
Hemolytic anemia
 Premature destruction of RBCs -
inherited defects/acquired
intravascular abnormalities.
 Hemolysis -Intravascular or extravascular
 General features of hemolytic anemia
General examination
Pallor, jaundice
Other physical findings
Splenomegaly, bossing of skull
Hemoglobin
Normal to severely reduced
MCV, MCH
Usually increased
Reticulocytes
Increased
Bilirubin
Increased (mostly unconjugated)
Haptoglobin
Reduced to absent
LDH
Increased( upto 10 times with intravascular
hemolysis)
Causes of hemolytic anemia
Heriditary
Intracorpuscular
Defects
Extracorpuscular
Factors
Hemoglobinopathies
Familial hemolytic
uremic syndrome (HUS)
Enzymopathies
Membrane-cytoskeletal
defects
Acquired
Paroxysmal nocturnal
hemoglobinuria(PNH)
Mechanical
destruction(microangiop
athic)
Toxic agents- clostridial
sepsis
Drugs
Infections-malaria
Autoimmune
Intravascular destruction of RBCs
Intravascular destruction of RBCs
schistocytes
Causes - mechanical trauma,
complement fixation,
toxic damage to the RBC.
Iron loss
Decreased serum haptoglobulin
hemoglobinemia
hemoglobinuria,
hemosiderinuria
Extravascular destruction of RBCs
Extravascular destruction of RBCs
Causes - bound
immunoglobulin, or
physical
abnormalities
restricting RBC
deformability that
prevent egress from
the spleen.
Iron overload leading to secondaryhemochromatosis-damage to liver& hear
Clinical features
Due to anemia
 Weakness, exhaustion & lassitude, indigestion, loss of
appetite
 Palpitations, giddiness, dyspnoea
 Pallor, hyperdynamic circulation, flow murmur
Due to hemolysis
 Icterus, splenomegaly in extravascular hemolysis, gall stone
disease
Lab investigations in hemolytic anemias
 Complete hemogram with reticulocyte count PBS – anemia
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with reticulocytosis & fragmented RBC on PBS
Decreased serum haptoglobulin.
LFT/KFT
DCT
USG abdomen- Hepatosplenomegaly
HPLC, Osmotic fragility test
RBC membrane structure
Membrane disorders-Hereditary spherocytosis
 MC -northern European ancestry
 AD, chr 8p
 Defect- abnormality of ankyrin.
 Decreased surface area/vol-
Spherocytes - less flexible –
extravascular hemolysis-splenomegaly.
 Only condition with increased MCHC.
 Increased osmotic fragility (Pink test)
 TT- No tt aimed at cause.
 Splenectomy – Obligatory .
 In pregnancy (rare)- fetal loss in 1st
trimester, aplastic or hemolytic crisis,
increased folic acid requirement due to
chronic hemolysis
 Splenectomy – 2nd trimester
 Affected Fetus – neonatal jaundice,
need for exchange transfusion
 PND- by CVS, amniocentesis
Normocytes, Spherocytes.
ENZYME DISORDERSG-6-PD deficiency
 MC enzyme deficiency .
 X linked recessive
 Mediterranean, West African, Mid-East,
and Southeast Asian populations
 Interaction between extracorpuscular &
intracorpucular cause.
 Heterozygotes - resistant to P falciparum.
 Oxidative stress- Increased methemoglobin, aggregates
of denatured hemoglobn to form heinz bodies, membrane
injury
 Screening – NADPH mediated dye decoloration
 Diagnosis – spectophotometric assay of NADPH
production, G6PD enzyme assays
Definite risk
Possible risk
Doubtful risk
Antimalarials
Primaquine,
Dapsone/chlorpro
guanil
Chloroquine
Quinine
Sulphonamides/
sulphones
Sulphametoxazole
Sulfasalazine,
Sullfadimidine
Sulfisoxazole,
Sulfadiazine
Antibacterial/
antibiotics
Cotrimoxazole,
Nalidixic acid,
Nitrofurantoin,
Niridazole
Ciprofloxacin,
Norfloxacin
Chloramphenicol,
p-Aminosalicylic
acid
Antipyretics/
analgesics
Acetamide,
phenazopyridine
(pyridium)
Acetylsalicylic
acid(high dose
>3g/dl)
Acetylsalicylic acid
<3g/dl.
Acetaminophen,
Phenacetin.
Other
Naphthalene,
Methylene blue
Vitamin K
analogues,
Ascorbic acid >1 g.
Rasburicase.
Doxorubicin,
Probenecid.
Contd…….
In pregnancy:
 Spontaneous abortion, still
birth & low birth wt babies
with neonatal jaundice
 Affected fetus – non
immune hydrops if mother
ingests oxidant drugs
crossing the placenta
 PND- CVS or FBS
 Avoid agents causing
hemolysis
 Acute hemolytic episode –
adequate hydration,
maintain urine output, BT if
needed
 spherocytes, schistocytes,
bite cells & blister*
Pyruvate kinase deficiency
 Autosomal recessive
 Reduced ATP formation causes RBC
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membrane rigidity.
PBS- polychromasia, anisocytosis,
poikilocytosis with burr cells &
acanthocytes
Symptoms -usually mild (right shift
of the 02-dissociation curve).
Homozygote -severe anemia &
usually discovered in childhood.
Splenomegaly, cholelithiasis and
jaundice .
In pregnancy – well tolerated,
supportive management during
crisis & BT if needed
Splenectomy – 2nd trimester
Fetus– nonimmune hydrops.
FBS for diagnosis & IUT if needed
MECHANICAL TRAUMA
 RBCs striking against
abnormal surfaces (aortic
stenosis, atherosclerosis) or
artificial surfaces (prosthetic
heart valves; arterial grafts).
 Microangiopathic hemolytic
anemia - RBCs torn apart on
fibrin strands strung across
small vessels or on damaged
endothelial surfaces of small
vessels.
 Accompanies DIC, malignant
hypertension, HUS, TTP,
pre-eclampsia, and some
vascular neoplasms.
GLOBIN SYNTHESIS
HEMOGLOBINOPATHIES
 Abnormalities due to
alteration in structure,
function or production of
hemoglobin
 inherited disordersautosomal dominant
(unstable hemoglobins)
and autosomal recessive
(Hgb S).
 The most common are
thalassemia and sickle cell
disease/trait.
 Minor disorders
Sickle cell trait- Hb AS
Hb SE disease
Hb SD disease
Hb S Memphis
 Major disorders
 Sickle cell anemia – Hb
SS
 Hb SC disease
 Hb S ß thal
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Sickle cell Disease
 Qualitative disorder
 Point mutation in the ß-chain at codon 6 encoding of a
valine instead of normal glutamin.
 Hb S- poorly soluble in low oxygen tension, polymerizes
into fibrilary structures/ tactoids-- causing them to
become rigid and sickled.
 M.C inherited hematological disease worldwide
 Most prevalent in African descent(1 in 625).
ACOG technical bullein, no. 185, Oct 1993
The term sickle-cell disease is preferred because it is
more comprehensive than sickle-cell anaemia.
Autosomal recessive
Homozygous/Heterozygous(coinheritance with other abnormal hemoglobin ;
mostcommonly HbSC or b thalassemia)
Diag -chances (for each pregnancy)of two carrier parents having a child with a
sickle cell or thalassaemia disorder.
If the mother is anemic & the father is healthy carrier 50% of the off springs
are carriers and 50% is anaemic
PATHOPHYSIOLOGY
 Hemolysis
 Vaso-occlusion-because of-
a)sickled cells are less deformable& more fragile & also
have increased tendency for cellular dehydration
b) Increased adhesion of red cells to vascular
endothelium(increased expression of adhesion
molecules, upregulation of thrombotic pathways,
proinflammatory state)
 Life span of sickle cells – 17 d
Initially, oxygenation restores normal shape.
With repeated cycles of agglutination &
polymerisation, sickling becomes irreversible
Diagnosis
 HIGH PRESSURE LIQUID CHROMATOGRAPHY
 Isoelectric focussing
 Cellulose acetate electrophoresis at
alkaline pH
 Capillary electrophoresis
 Sickle cell solubility test- Widely used
screening method.
 Relies on the relative insolubility of Hgb S in concentrated
phosphate buffers compared to Hgb A and other Hgb
variants. Hgb S precipitates causing a cloudy solution.
Sickle cell trait
 Hgb SA- 25 - 45% of the hemoglobin is Hgb S;
remainder being Hgb A, Hgb F & Hgb A2.
 No anemia and normal RBC morphology is the
rule.
 Two rare complications-hematuria and splenic
infarction.
 No risk from anesthesia, surgery, pregnancy, or
strenuous physical activity.
 Normal growth & development, normal life spans
 Increased incidence of pre-eclampsia in
pregnancy
Preconceptional care
General advice & care  At least annual review at specialist clinic  BP measurement,
 KFT testing,
 ophthalmological checkup,
 screening for red cell antibodies & iron overload*,
 cardilogy review for pulmonary hypertension( echo not
done in last year)
o Specific issues in women trying to conceive-
counselling about
 Risk of worsening anemia, increased infections(especially UTI),
pain, IUGR, PTL, Pre-eclampsia , caesarean section & perinatal
mortality.
 Role of dehydration(Early detection & treatment of nausea
&vomiting), cold, hypoxia, overexertion, &stress in frequency of
sickle cell crisis
Pregnancy
Offer screening
Blood sent to laboratory for haemoglobinopathy Screen
ANTENATAL SCREENING
Negative Result
Information: No further action
Positive results
Information & counseling-Offer partner screening
Partner screening
Blood sent to laboratory for haemoglobinopathy Screen
Negative Result
Information: No further action
Positive results: At risk couple
Information & counseling-Offer prenatal diagnosis
Prenatal diagnosis
Fetal blood Sampling/ Chorionic Villus sampling
Unaffected Fetus
Information- No further action
Affected fetus- Information &counseling
Parents Make- Informed Choice
Termination of Pregnancy
Continue with Pregnancy
Sickle cell disease contd….
 Medications-Daily penicillin prophylaxis (250 mg BD)
 Folic acid 5mg once daily throughout pregnancy
 Hydroxycarbamide should be stopped 3 months prior to
conception( termination is not indicated based on
exposure to hydroxycarbamide alone).
 ACE inhibitors & Angiotensin 2 receptor blocker , iron
chelating agents should be stopped
 NSAID’s are not recommended <12weeks& >28 weeks ;
should only be taken after medical advice in 2nd trimester.
 Vaccinations ( preconceptional)*-H.influenza type b,
conjugated meningococcal C vaccine, Hepatitis B ,
Influenza & swine flu vaccine annually, pneumococcal
vaccine every 5 years.
Management of sickle cell Disease in pregnancy. RCOG2011
Sickle cell disease contd….
 Indications of urgent transfusion therapy1) Acute anemia - top up transfusion,
 Hb <6 g/dl or
 a fall of over 2g/ dl or
 symptomatic patients.
2)Acute chest syndrome& acute stroke – exchange
transfusion
Role of prophylactic transfusion in pregnancy Insufficient evidence to draw the conclusion about role of
prophylactic blood transfusions in pregnancy.
Mahomed K et al. prophylactic versus selective blood transfusion for sickle cell
anemia.2006. The cochrane library, issue 2.
 Indicated for women who are on a long term transfusion
regime prior to pregnancy.*
Antenatal care
 Multidisciplinary team
 Pregnancy – exacerbations of disease manifestations
 increased metabolic demands,
 hypercoagulable state,
 increased vascular stasis –
 Vaso-occlusive crisis – common in later half of pregnancy
 Pyelonephritis – altered immune system added to renal
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changes of pregnancy
Symptomatic cholelithiasis – chronic hemolysis,
progesterone induced changes in GIT
Susceptible to infections, pre-eclampsia,thromboembolism
IUGR, preterm labour, abruption,
SCREENING – selective (low preevalance area) versus
universal(high prevalance area) mainly to diagnose minor
forms. If positive, screen partner, genetic counselling, PND
Antenatal management
 Early booking
 ANC Visits monthly upto 24weeks, 2weekly until 36weeks&
weekly thereafter.
 Low dose aspirin (75mg daily )from early
pregnancy(12weeks) till 28weeks.
 Routine thromboprophylaxis only if they have additional
risk factors, but should receive LMW heparin during
antenatal hospital admission.
RCOG 2009. Reducing the risk of thrombosis in pregnancy & puerperium.
Green top guideline 37.
Role of iron suplementation:
 Iron supplementation is withheld unless there is e/o iron
deficiency.
Akien’ova YA et al. Ferritin & serum iron levels in adult patients with sickle cell
anemia in Ibadum, Nigeria. Afr J Med Sci1997;26.
Contd……….
 Routine iron supplementation entails a negligible theoretical
risk of iron overload for a substantial benefit.
Streetly A et al, BMJ 2000; 320.
 BP & Urinalysis at each visit.
 Serial USG for GP & AFI from 24 weeks; every 4 weekly& more
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frequently if there is evidence of poor growth.
Monthly assessment of hct, reti count, urine c/s
Fetal monitoring – DFMC, weekly NST & BPP
Maintain oral hydration, diagnose & treat infections early
Mode of delivery- In the absence of obstetric indications
allow spontaneous labour at term
Role of cytotoxic agents to HbF & HbA – 5-azacytidine,
hydroxyurea – investigational in pregnancy.
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Management of acute painful episodes
during pregnancy
 Most frequent complications, incidence- 27%-50%.
 Mild pain –rest, fluids & simple analgesia(paracetamol& week opoids)
 Severe pain- low threshold for admitting to hospital.
 Assess for other complications precipitating factors(Dehydration)
 Ix-spo2, urinalysis, full blood count, reticulocyte count, KFT, Urine
c/s, blood c/s, chest x-ray.
 Tt- strong opoids- morphine/ diamorphine(oral/parenteral) are the
first line agents.
 Give adjuvant non-opoid analgesia: PCM, NSAIDS(12-28weeks)
 Monitor for pain score, sedation score, & oxygen saturation using
a modified obstetric early warning chart(MEOWS), RR every 2030minutes until pain is controlled & signs are stable, then monitor
every 2 hour or hourly if receiving parenteral opiates.
 Give rescue dose of analgesia if required.
Rees DC et al. Guidelines for the management of acute painful crisis in sickle cell disease.
BJH. 2003;120.
Contd…
 If RR<10/min, omit maintenance analgesia; consider
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naloxone
Oral/ iv fluids – 60 mg/kg/24 hours.(precaution – PET)
Maintain I/o chart
Antibiotics & Thromboprophylaxis should be used.
Consider reducing analgesia after 2-3days & replacing
injections with equivalent dose of oral analgesia.
Discharge when -pain is controlled/ improving without
analgesia or on acceptable doses of oral analgesia.
Rees DC et al. Guidelines for the management of acute painful crisis in sickle cell disease.
Br J Hematol 2003;120.
Intrapartum management
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Timing of delivery- 38-40 weeks.
Mode of delivery- vaginal.
Adequate hydration
Pulse oxymetry should be used throughout labour
Supplemental oxygen therapy used if necessary to maintain
spo2 >94%.
Antibiotic therapy should be used if there is evidence of,
or high clinical suspicion of infection.
Continuous fetal monitoring
Epidural analgesia
Regional anaesthesia preferred for caesarean section.
Hourly vital signs- low threshold to start broad spectrum
antibiotics
Management of sickle cell Disease in pregnancy. RCOG2011
Post partum management
 Risk of thrombo-embolism, painful crisis
 Early ambulation, hydration,pain releif (NSAIDS/pcm/
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opoids)
Prophylactic sucutaneous LMW heparin for 7 days after
vaginal delivery & 6 weeks following a caesarean section.
Aggressive treatment of suspected infection
Cord blood – HPLC
Encourage breast feeding
Antithrombotic stocking
Baby affected- prophylactic penicillin from 3 months of
age- ↓ incidence of pneumonia.
Contraception- progesterones are effective & safe
contraceptive . First line- PIC, MIRENA, Implanon, pop,
barrier method. Second line- COC, Cu- IUD, Vaginal ring ,
Combined patch.
THALASSEMIAS
 Imbalance of globin chains available for hemoglobin dimer
construction.
 ß thalassemia - defective synthesis of the ß chain.
 A thalassemia, defective synthesis of the a chain
(quantitative).
 Globin chain (a, b, d, e, g & z) structural genes are located
on chromosome 16 (a;z) and chromosome 11 (b;d ; e;g).
Geographic distribution
 ß -thalassemia is common in the Mediterranean region, Africa, Asia,
the South Pacific, and India.
 a -thalassemia more common in Southeast Asia.
 Prevalance- 16% in southern European , 10% in Thiland , 3-8% in
Indian , Pakistani & Bangladeshi population
Leung TN et al. Thalassemia screening in pregnancy.Curr Opin Obstet Gynecol 2005; 17.
ß-Thalassemia
 point mutations or a partial deletions of chromosome 11 cause
defective synthesis of the ß chain.( >100 mutations)
 Normally- a and b globin chains are roughly equal amounts.
 When ß-globin chains are in short supply or absent, the excess achains combine with other available ß-family globin chains ( d or
g) to form increased amounts of Hgb A2 (a2d2) & HgbF (a2g2).
 Hgb Barts( g4) or tetramers of excess gamma chains may form.
 The clinical severity
depends on the degree to
which production of the ßchain is inadequate.
 ß-thalassemia major -no
ß chains (ßo) or very little
is made (ß+).
 ß-thalassemia minor ß+ chains are made in
mildly reduced amounts.
 ß+thalassemia
intermedia ß+ chains are
made in amounts
intermediate to the major
and minor forms.
Signifcance of ß-gene
Mutation
 type 1 ß+ - about 10%
of normal ß chain
production
 type 2 ß+ -about 50%
of normal ß chain
production
 type 3 ß+ - >50%
of normal ß chain
production
ß-Thalassemia major
 No ß chains (homozygous for ßo, Cooley's
anemia), or very little ß chain (homozygous
for ß+).
 Hgb electrophoresis-↑ HbF,↑ HbA2,
variable amounts of Hb A.
 PBS - severe anisocytosis& poikilocytosis,
targets, elliptocytes, teardrops
 Asymptomatic till 6 months of life**
 C/F- severe, transfusion dependent anemia.
Nearly all have hepatosplenomegaly.
 Expansion of the marrow by erythroid
hyperplasia - enlargement of bones.
 Iron overload, secondary to transfusion
dependency, results in damage to the heart,
liver and endocrine organs.
 Short life span, most dying before
adulthood.
ß-Thalassemia minor
 ß-thalassemia trait/ minor-
Heterozygous- mildly reduced
production of ß+ chains & thus, a
mild excess of a globin chains which
denature, causing damage to young
PBS- microcytic &
red cells in the marrow (ineffective hypochromic; often with
erythropoiesis) or decreased
associated erythrocytosis
survival in the peripheral blood.
 ß-thal intermedia mb homozygous
Basophilic stippling
for type 2 ß+ and type 3 ß+.
and reticulocytosis
 Mild anemia
may help to
 High Hemoglobin A2 levels are
distinguish the bclassic. Hb F - mildly increased.
thal minor & fe def
 Folic acid 1mg/d to be supplementedanemia(more
common in
thalassemia).
a -Thalassemia
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Classical a-thal- deletion from chromosome 16 of a-genes.
Less common is point mutations.
Exess ß-chains form pairs and combine to form HbH (ß4).
Unpaired ß chains precipitate, damages RBC membrane.
Severity vary with the number of alpha-chain genes
deleted
a -Thalassemia
• One alpha gene deleted- silent carrier state.
 Two alpha genes deleted-homo/heterozygous
a -thalassemia trait.
 a-thalassemia trait - microcytosis,
hypochromia, & mild anemia. Normal HbA2
 3 genes deleted:( - - /-a) hemoglobin H is
produced (four ß chains) - unstable &
precipitates in vivo causing hemolysis.
Crystal violet/new methylene blue supravital
stains- Heinz bodies (precipitated Hgb H).
 All 4 genes deleted- Bart's hemoglobin-
tetramer of g chains - hydrops fetalis- death
in utero - encountered in people of Asian
and African ancestry.
Thalassemia screening
 Incidence- very high, with over 30 million people carrying
the defective gene. Carrier frequency varies from 3 to 17%
in different populations
 Over 9000 thalassemic children born every year &
treatment is very expensive
 Carrier screening program offers genetic counselling, PND
and selective termination of affected fetuses.
 Various options available are:
 Screening of school going children;
 Screening of high risk communities;
 Premarital screening;
 Extended family screening - screening of relatives if
there is a thalassemic child in a faimly; and
 Routine antenatal screening in early pregnancy ideally
between 10-12 weeks(Most faesible)
Menon P.S.N et al, dept of paeds, AIIMS
Methods of Antenatal screening
 RBC indices:MCV (<77 fl) and MCH (<27 pg) with
sensitivity98% and specifity92%.
 NESTROFT: Positive test is due to the reduced osmotic fragility
of red cells .
 sensitivity – 91%, specificity-95%, ppv-55% & npv-99%.
 Raised Hb A2 level >3.5%: Gold standard
Methods- Microcolumn chromatography, HPLC and capillary
isoelectrofocusing.
 16% of ANC were positive by NESTROFT
 & RBC indices. However, only 4.5% were
 confirmed by HbA2
Unpublished data, ICMR project, dept of paeds, AIIMS
contd
 When MCH/MCV is low, check both hb pattern &
iron status.
 HPLC- HbH inclusion bodies – diagnostic of alpha
thalassemia trait.Beta thal trait – HbA2 &HbF
both are elevated.
 False negative- carrier of both alpha & beta
thalassemia, associated iron deficiency. Therefore
a normal Hb pattern in presence of iron deficiency
can not exclude a co-existing thalassemia trait. A
repeat HPLC after correction of iron deficiency
should be done.
Non-invasive prenatal diagnosis
 Unlike beta- thalassemia, alpha thalassemic fetuses present
from early gestation with anemic signs ; detectable on USG:
safe alternative in prenatal diagnosis.
 USG surveillance for couples with alpha thalassemia –
cardiomegaly, thickened placenta, increased MCA-PSV, &
Hydropic changes.
 CTR is the best marker in first trimester.Between 12-15
weeks –using CTR 50% or greater as cut off, Sn 97.5%, Fp
9.1%. Placental thickness ≥ 18mm- Sn- 71%. Fp- 19%.
 2nd trimester- CTR is still the best marker( Sn -100%, Fp5.9%.
Leung KY et al.Ultrasonographic prediction of homozygous alpha thalassemia using
placental thickness, fetal CTR, MCA doppler: alone or in combination? Ultrasound Obstet
Gynecol2010;35.
Noninvasive prenatal diagnosis for
couples with beta thal
 USG- Not applicable
 Analysis of circulating fetal nucleic acid in maternal
plasma- most specific
 absence of paternal mutation in maternal plasma excludes beta
thal major & invasive testing can be avoided.presence of paternal
mutation in maternal plasm- 50% risk of beta thal major;
invasive testing needed.(Disadv- father & mother must carry
different mutation)
 When dealing with other paternally inherited beta-gene defect
involving point mutation, allele specific/ single allele extension
reaction followed by mass spectrophotometry.
Lo YM et al. Noninvasive approaches to prenatal diagnosis of
hemoglobinopathies using fetal DNA in maternal plasma.Hemaatol
Oncol Clin North Am 2010; 24.
 Digital PCR combined with fetal DNA enrichment
strategy- Allelic ratio-1:1-carrier, >1- fetus homozygous for
mutation, <1- fetus has not inherited any mutation.
Lun et al.Noninvasive prenatal diagnosis of prenatal monogenetic disease by digital
size selection and relative mutation doses on DNA in maternal plasma. Prac Natl
Acad Sci U S A 2008;105.
 Most recent- application of massively parallel DNA
sequencing technologies in cell free fetal DNA in maternal
plasma.
Lo YM et al. Maternal plasma DNA sequencing reveals the genome-wide genetic &
mutational profile of fetus. Sci Transl Med 2010;2.
 Pre-implantation genetic diagnosis- cleavage stage
biopsy is better than polar body / blastocyst biopsy.
Petrou et al.Preimplantation genetic diagnosis. Hemoglobin 2009; 33:s7-s13
Maternal health & Obstetric outcome
Assessment &management of pre-existing
complications
 Cardiac effects
 Endocrine problems
 Alloimmunisation
 Assessment & treatment of viral infections
 Hypercoagulable state & thrombosis
 Effect of hemolysis & depletion of nitric oxide
 Osteopaenia, osteoporosis & bone deformity
 Pre-pregnancy assessment & management.
Beta- thalassaemia major & intermedia
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Spontaneous miscarriage & fetal loss- 9%-33%.
Preterm birth- increased
Multiple pregnancy- higher incidence
Fetal growth restriction-increased because of maternal
anemia & reduced oxygen supply.
Obstetric complications- gestational hypertension & preeclampsia (most frequent; 2.5%- 20%); gestational
diabetes (10-20%); placental abruption(3.8%-6.7%);
UTI(3.8%)
Maternal cardiac failure-1.1%-15.6%
Caesarean delivery- high(high rate of CPD, maternal
short stature, oseopaenia/ osteoporosis & maternal HIV
infection,low threshold for caesarean delivery*
Contd……..
Maternal anaemia and transfusion of red blood cells-
target Hb-10gm/dl
Prophylaxis for thromboemboism- no specific regime.
Acetylsalicylic acid antenatally for women who have
undergone splenectomy & postpartum LMW heparin.
Lam YH et al.Risk of neural tube defects in offspring of thalassaemia carriers in
Hongcong Chinese. Prenat diag 2006.
Thalassaemia trait-Screening for fetal congenital
anomalies, especially neural tube defects-in alpha &
beta thalassaemia carrier anencephaly was more
common(OR 3.99).
Tong et al. C-reactive protein & insulin resistance in subjects with thalassaemia major &
family history of diabetes. Diabetes Care 2002; 25.
Contd……
 Gestational glucose intolerance-markedly increased.
Mechanism increased insuline resistance in liver & muscle,
 low grade hepatic inflammation ,
 increased oxidative stress secondary to hepatic damage
from the increased iron owing to low grade hemolysis.
Origa R et al. Pregnancy and beta thalassaemia: an Italian multicenter experience.
Hematologica 2010; 95.
Antanatal complications IUGR(OR 2.4)
 Oligohydroamnios (OR 2.1)
 Hydrops fetalis & mirror syndrome- can result as a result of
hemoglobin Bart’s disease & non-deletional form of hemoglobin
H disease.
Autoimmune hemolytic anemia
• Most common form of aquired hemolytic anemia( exept where
•
•
•
•
•
•
•
•
malaria is endemic)
Autoantibody directed against red cells
Triad- abrupt onset, jaundice, splenomegaly.
Coomb’s test- Positive- clinches diagnosis; Negative- diagnosis
unlikely.
Two types: a) IgG or "warm" type (optimally active at 37oC)
b) IgM or "cold" type (optimally active at 4oC)
Treatment- 1st line- Glucocorticoids- prednisone- 1mg/kg/day
Second line- low dose prednisone, azathioprine, cyclosporine.
Severe acute AIHA- blood transfusion
Cold AIHA
 IgM Ab, optimally active at 4oC
 Causes - Iymphoma, Mycoplasma pneumonia& rarely
infectious mononucleosis
 IgM- C3 complex fixation on the RBC surface at 28-31oC.
 RBC agglutination and hemolysis in acral cold exposed
areas of the body.
 Intravascular hemolysis
 Detected by the DCT.
 PBS-agglutination of RBCs
(room temperature).
 Antibody does NOT cross placenta, fetus is NOT affected
Warm AIHA
 IgG antibodies against RBC surface Ag (active at 37°C).
 Causes- Non-Hodgkin's Iymphomas, Hodgkin's disease,
autoimmune disorders (rheumatoid arthritis; SLE)& drugs
(methyl dopa)
 PBS - Prominent spherocytosis
 Positive DCT (direct Coombs' test).
 Treatment ( warm or cold):
1) treatment of the underlying disease,
2) discontinue offending drugs, &
3) corticosteroids (Prednisone).
 Antibody may cross placenta & affect fetus
Paroxysmal nocturnal hemoglobinuria
 Clonal disorder of gene (PIG-A) encoding
GPI anchor
 Proteins requiring GPI anchor to attach to
the RBC membrane are deficient - DAF, C8bp, MIRL.
 Bone marrow - usually cellular with
marked to massive erythroid
hyperplasia, with mild to moderate
dyserythropoietic features
 Iron deficiency - chronic loss of iron in urine.
 Blood instead of urine
 Most consistent- anemia.( m.b
Pancytopenia).
 Hypercoagulable state- venous thrombosis
(Budd chiari syn – MC cause of death)
 Gold standard- Flow cytometry( CD59-,
CD55-)
 Rx- Allogenic BMT ; eculizumab.
Pregnancy & PNH
o Fertility is low, 15 pregnancies reported in 10 patients-
5 SA, 10 reached viability- good outcome
o ? Prophylactic washed RBC transfusions
o Folic acid supplementation(3 mg/day)
o Steroids to ↓hemolysis in acute episode
o BT may be needed
o BMT, androgens – No role in pregnancy
o Postpartum thrombotic events are common &
complete anticoagulation with warfarin is needed
Aplastic anemia
o Failure of pluripotential stem cells to produce RBC, WBC,
platelet.
o pancytopenia + hypocellular bone marrow& absence of
underlying malignant/myeloproliferative disease.
o Severe aplastic anemia- pancytopenia with two of theseANC< 500/ dl,
Platelet count< 20,000/dl&
Anemia with Reticulocytes < 1% ,
with either bone marrow cellularity
<25% or cellularity >50% with <30%
hematopoietic cells.
Diagnosis & treatment of aquired aplastic anemia. Hematol oncol clin N Am 2009, 159-170.
o Pure red cell aplasia- progenitor cell of BFU-E is affected.
o Incidence- 2 cases per million(Europe)
Choudhary vp et al. Pregnancy associated aplastic anemia –a series of 10cases with review
of literature. Hematology 2002.
Aplastic anemia
o Pregnancy- increased placental lactogen,
erythropoietin & estrogen. Placental lactogen &
erythropoietin stimulates erythropoiesis estrogen
supresses bone marrow. Pregnancy exacerbate the
bone marrow depression – if so, terminate
pregnancy; else supportive treatment
Pregnancy with aplastic anemia serious condition.
o Maternal mortality- 20-50%
o Cause of death- Hemorrhage & infection.
o Women who survive pregnancy –associated aplastic
anemia , 50-70% achieve spontaneous remission
Choudhary vp et al. Pregnancy associated aplastic anemia –a series of 10cases with
review of literature. Hematology 2002;7.
Causes
1) Radiation
2) Viruses- parvovirus; hepatitis (non-A, non3)
4)
5)
6)
B);EBV, HIV-1.
Drugs- marrow suppressive chemotheraputic
agents -alkylating agents; antimetabolites
-chloramphenicol; quinacrine; phenylbutazone;
gold; hydantoin
Chemicals/Toxins- benzene; weed
killers/insecticides; arsenic, glue sniffing
Immune disorders- SLE, thymoma
Idiopathic
Harrison’s textbook of internal medicine, 17th ed
Aplastic anemia & pregnancy
Maternal
 Antenatal complications-
Preterm birth- 12.1%
IUD- 16.7%
Stillbirth- 15.1%
Spontaneous miscarriage- 16.7%
 Intrapartum- Risk of hemorrhage during delivery
 Postpartum- risk of hemorrhage & infection.
Fetal- IUGR, IUD, Fetal thrombocytopenia, rarely gangrene
of fetal intestine.
Kown et al. Supportive management of pregnancy associated aplastic anemia.
Int J Gynecol Obstet 2006.
Treatment
 Supportive therapy- Most important
 Repeated blood transfusion to maintain Hb>8 mg/dl
 Platelet transfusion yo maintain platelet count > 20,000/mcl.
 WBC transfusion can be considered in case of fulminating
infection
 Antibiotic & barrier nursing.
 Early stages -First line therapy - erythropoietin &GM-CSF.
 If it fails - thymocyte gamma globulin & cyclosporine
 G-CSF & GM-CSF can be used in for neutropenia/infection
 BMT- Most effective . 5 year survival rate 70-80%
 BMT is contraindicated in pregnancy
 Androgen is relatively contraindicated.
Deka D et al. Pregnancy associated aplastic anemia: Maternal & fetal outcome. J Obstet
Gynecol Res 29, 2003.
ANEMIA OF CHRONIC DISEASES
 Underlying disease - inflammation, infection, or
malignancy
 usually mild(Hct 30-40%)normochromic/normocytic,
Occ mildly hypochromic/microcytic
 Low serum iron, normal or low transferrin, low
transferrin saturation, and high serum ferritin. Bone
marrow iron stores are usually increased.
 Ferritin(acute phase reactant)- elevated in
inflammation.
 Primary mechanism - decreased red blood cell
production.Inflammatory and infectious disorders
release factors (IL-1, tumor necrosis factor) that
suppress erythropoiesis.*
 Treatment of the underlying disease.
 Inappropriately low serum erythropoietin levels for the
degree of anemia. Human recombinant erythropoietin
(EPO) therapy can correct the anemia in such cases.
Thrombocytopenia
 Platelet count below 1lakh
 Affects 10% of all pregnancies
 Platelet count decreases by 10% in normal pregnancies
 Mostly physiologic
 Most common causes-
Gestational thrombocytopenia(70%),
preeclampsia(21%),
ITP(3%)& others(6%)
 Mild thrombocytopenia- PC >65000/mcl: 65% have no
associated pathology.
Paula L et al.Thrombocytopenia in pregnancy. Hematol Oncol Clin N Am 25 (2011)
ITP
Immune Thrombocytopenia
Diagnosis of exclusion
Incidence- 0.1-1 per 1000 pregnancies
Most common cause of isolated thrombocytopenia in
1st & early 2nd trimester.
Pathogenesis:
Autoantibody
platelet
destruction
Immune mediated
decreased platelet
production
Nugent D. Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction
&/or decreased platelet production. Br J Hematol 2009;146.
ITP
 H/o- easy bruisability, epitaxis, petechiae, menorrhagia
before pregnancy, thrombocytopenia in prior pregnancy,
 PBS- Thrombocytopenia with an increased mean platelet
volume & normal red cell morphology.
 Lab ix- CBC, Reticulocyte count, PBS, Coagulation screen,
LFT, & Virology screen including Hepatitis C.
 Exclude spurious thrombocytopenia
 Others- Kft, DCT, TFT, autoimmune profile,
antiphospholipid antibodies.
 Bone marrow biopsy-indicated in minority of cases only.*
Causes of maternal thrombocytopenia
Isolated thrombocytopenia Asso with systemic disorder
 Spurious
 Gestational
 Primary ITP
 Drug induced- alcohol,
Consumption of quinine( tonic
water), exposure of
environmental toxin.
 Congenital – Thrombocytopenia
absent radius syndrome,
Radioulnar synostosis, wiskott
Aldrich syndrome, Bernard Soulier syndrome, Type Iib
VWD.









Preeclampsia & HELLP syndrome
Acute fatty liver
HUS
TTP
SLE
Thyroid disease
Antiphospholipid syndrome
DIC
Viral infection- HIV, EBV, CMV, HBV,
HCV.
 Folate deficiency
 Hypersplenism
 Coincidental marrow disease- MDS,
Leukemia, Aplastic anemia
Gestational thrombocytopenia
 Commonest cause of thrombocytopenia in healthy
pregnant women
 Featureso Tendency to recur in each pregnancy(20%),
o typically in 2nd trimester,
o Platelet count remains > 70,000/L,
o Neonatal platelet count remains normal, &
o Postpartum platelet count returns to normal within 7 days.
 PBS- No abn.
 No associated increased incidence of maternal bleeding
 No indication for therapy
Sankaran & Robinson. ITP & Pregnancy. Obstetric medicine 2011.
Management of ITP in pregnancy
 Preconceptional counselling
 Antenatal management- Team work.
 Treatment to be initiated when platelet count falls <20-
30000/mcl.
 Asymptomatic & PC>50000/mcl- No treatment required.
 < 50000/mcl & symptomatic- treatment to be considered.
 >50000 but<70000- Consider treatment if – neuaxial
anaesthesia/ analgesia or elective LSCS due to obstetric
indication is to be considered.
 Neuraxial anaesthesia/ analgesia-contraindicated if platelet
count <50000/mcl.
 Caesarian delivery is safe if platelet count is > 50000/mcl.
Provan D et al. International consensus report on the investigation & management of primary
Blood 2010; 115.
Management of ITP in pregnancy
First line therapy Corticosteroids- oral prednisolone 1mg/kg once daily ;
initial response 3-7 days & maximal response in 2-3 weeks.
 MOA- To block antibody production& to reduce
phagocytosis of antibody-coated platelets by RE system in
the spleen.
 Fetal s/e- risk of cleft palate 3 per 1000.
 Maternals/e- Hyperglycemia, hypertension,
immunosuppression, osteoporosis on long term use
 Lactating mother – low dose <30mg/day appears safe.*
 Baseline immunoglobulin profile to exclude a common
variable immunodeficiency prior to a trial of steroid is
recommended.
Provan D et al. International consensus report on the investigation & management of
primary ITP. Blood 2010; 115.
Contd……
 Immunoglobulin- 2 g/kg iv divided over 2-5 days.
Adv- rapid response,
Disadv- transient response(1-4 weeks), expansive, risk
of pathogen transmission, infusion reaction, aseptic
meningitis, hedache.
 Second line options- combination therapy with high
dose methylprednisolone combined with Ivig in
refractory cases. Azathioprine 2mg/kg, in refractory
cases(disadv- delayed response- 6-8 weeks).
Splenectomy – rarely needed.
 Platelet transfusion is NOT indicated exept- severe
hemorrhage, immediately before surgery/ delivery.*
Provan D et al. International consensus report on the investigation & management of
primary ITP. Blood 2010; 115.
ITP in pregnancy
 Mode of delivery – guided by obstetric need. Vaginal
delivery preferred.
kelton et al.Idiopathic thrombocytopenic purpura complicating
pregnancy. Blood Rev 2002; 16.
 Instrumental delivery should be avoided
 Management of unexpected delivery, emergency
intervention or hemorrhage- combination of high
dose intravenous methylprednisolone 0.5-1g daily for
2-3 days & 2g/kg total dose iv ig over 2-3 days with/
without platelet support& oral/iv tranexamic acid.
Contd…..
Postpartum-
 Maternal- NSAIDs & IM injections to be avoided.
PC>50000& absence of bleeding elsewhere thromboprophylaxis to be considered.
 Neonatal cord blood platelet count ( if low, confirm it by venous sample)
 If PC <50000 at delivery –
 oral vit-k 2mg at birth, 2mg at one week, 2mg at 1 month(instead of
im vit k).
 Transcranial USG,
 Alternate day platelet count.
 If hemorrhage is evident/neonatal platelet count is <20000,
treatment is ivig 1g/kg infusion; repeated if necessary. Platelet
support may be needed.
Sankaran & Robinson. ITP & Pregnancy. Obstetric medicine 2011.
Hemophilia
 X-Linked recessive
 Hemophilia-A- Deficiency of factor viii
 Hemophilia-B- Deficiency of factor ix
 Classified as mild 6-30%.


moderate 1-5%,
severe<1% residual activity,
 Prolonged APTT
 Diagnosis- factor assay.
 Tt- Factor replacement therapy( recombinant factor viii/ ix).
 Others- Cryoprecipitate, DDAVP, Tranexamic acid, EACA
Prenatal diagnosis for carriers of
haemophilia
Prenatal testing
Timings(weeks
POG)
Risk of
Comments
miscarriage(%)
Non-invasive determinations of fetal gender
ffDNA
≥6-8Weeks
-----
Currently only available
in certain centres
USG
11-14Weeks
-----
First- trimester USG fetal
sexing available at certain
centres
Prenatal diagnosis of haemophilia
ffDNA
≥6-8Weeks
-----
Under research
CVS
11-14
1-2
Known causative
mutation
Amniocentesis
≥15weeks
1
Known causative
mutation
Cordocentesis
18-2o
1-2
Causative mutation
Hemophilia contd….
 Antenatal- PND- fetus affected; consider for MTP.
 assess factor level at booking, 28weeks& at 34weeks POG.
Consider for planned delivery.
 Intrapartum- prophylactic cover is recommended for
women with Vwf, FVIII, FIX levels <50iu/dl at term, & they
should be maintained above this level for at least 3 days
after vaginal delivery / 5 days after caesarean section.
 Delivery by least traumatic method; Meticulous
hemostasis
 No invasive fetal monitoring
 Postpartum- risk of PPH
 Neonatal- Cord blood sample to assess coagulation status
& clotting factor level.
Pregnancy can be a time of
significantly increased morbidity &
mortality in women with
hematologic disease; however,
with careful planning &
preparation, most women can be
cared for safely, resulting in
“Healthy Mother& Healthy Child”
Thank you

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