Hematological disorders in pregnancy

Guide- Dr. Neeta SinghCO-guide- Dr. Sujata Rawat

Candidate- Dr. Prerna

Headings Disorders of RBC’S – Anemia, Hemoglobinopathies &

polycythemia Disorders of WBC’s Disorders of Platlets Coagulation disorders – Inherited/Aquired Hematological malignancies

Anemia

ANEMIAS OF DECREASED RBC PRODUCTION

ANEMIA DUE TO RBC DESTRUTION

DECREASED Hb SYNTHESIS- MICROCYTIC IRON DEFICIENCY THALASSEMIA SIDEROBLASTIC ANEMIA

DECREASED DNA SYNTHESIS- Megaloblastic anemia

STEM CELL FAILURE – Aplastic anemia

ANEMIA OF CHRONIC DISEASE

Hemolytic anemiaAutoimmuneHemoglobinopathies

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 anemiaIntracorpuscular Defects

Extracorpuscular Factors

Heriditary Hemoglobinopathies Familial hemolytic uremic syndrome (HUS)

Enzymopathies

Membrane-cytoskeletal defects

Acquired Paroxysmal nocturnal hemoglobinuria(PNH)

Mechanical destruction(microangiopathic)

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.

Decreased serum haptoglobulin, hemoglobinemia hemoglobinuria, hemosiderinuriaIron loss

Extravascular destruction of RBCs

Extravascular destruction of RBCsCauses - bound immunoglobulin, or physical abnormalities restricting RBC deformability that prevent egress from the spleen.

Iron overload leading to secondaryhemochromatosis-damage to liver& heart

Clinical featuresDue to anemiaWeakness, exhaustion & lassitude, indigestion, loss

of appetitePalpitations, giddiness, dyspnoeaPallor, hyperdynamic circulation, flow murmurDue to hemolysisIcterus, splenomegaly in extravascular hemolysis,

gall stone diseaseLab investigations in hemolytic anemiasComplete hemogram with reticulocyte count PBS –

anemia with reticulocytosis & fragmented RBC on PBS

Decreased serum haptoglobulin.LFT/KFTDCTUSG abdomen- HepatosplenomegalyHPLC, Osmotic fragility test

RBC membrane structure

Membrane disorders-Hereditary spherocytosis

MC -northern European ancestryAD, chr 8pDefect- 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 trimesterAffected Fetus – neonatal jaundice,

need for exchange transfusionPND- by CVS, amniocentesis

Normocytes, Spherocytes.

ENZYME DISORDERS-G-6-PD deficiencyMC enzyme deficiency .

X linked recessiveMediterranean, 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 decolorationDiagnosis – spectophotometric assay of NADPH

production, G6PD enzyme assays

Definite risk Possible risk Doubtful risk

Antimalarials Primaquine, Dapsone/chlorproguanil

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*

Autosomal recessive Reduced ATP formation causes

RBC 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 trimesterFetus– nonimmune hydrops.

FBS for diagnosis & IUT if needed

Pyruvate kinase deficiency

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

HEMOGLOBINOPATHIESAbnormalities due to

alteration in structure, function or production of hemoglobin

inherited disorders- autosomal dominant (unstable hemoglobins) and autosomal recessive (Hgb S).

The most common are thalassemia and sickle cell disease/trait.

Minor disordersSickle cell trait- Hb

ASHb SE diseaseHb SD diseaseHb S Memphis

Major disordersSickle cell anemia –

Hb SSHb SC diseaseHb S ß thal

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.

Diag -chances (for each pregnancy)of two carrier parents having a child with a sickle cell or thalassaemia disorder.

Autosomal recessiveHomozygous/Heterozygous(coinheritance with other abnormal hemoglobin ;mostcommonly HbSC or b thalassemia)

If the mother is anemic & the father is healthy carrier 50% of the off springs are carriers and 50% is anaemic

PATHOPHYSIOLOGYHemolysisVaso-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 dInitially, 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 careGeneral 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

ANTENATAL SCREENING Pregnancy

Offer screeningBlood sent to laboratory for haemoglobinopathy Screen

Positive resultsInformation & counseling-Offer partner screening

Partner screeningBlood sent to laboratory for haemoglobinopathy Screen

Positive results: At risk coupleInformation & counseling-Offer prenatal diagnosis

Affected fetus- Information &counseling

Parents Make- Informed Choice

Termination of Pregnancy

Prenatal diagnosisFetal blood Sampling/ Chorionic Villus sampling

Negative ResultInformation: No further action

Unaffected FetusInformation- No further action

Negative ResultInformation: No further action

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 therapy-

1) 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

manifestationsincreased metabolic demands, hypercoagulable state, increased vascular stasis –

Vaso-occlusive crisis – common in later half of pregnancy

Pyelonephritis – altered immune system added to renal 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 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 20-30minutes 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

naloxoneOral/ 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 managementTiming of delivery- 38-40 weeks.Mode of delivery- vaginal.Adequate hydrationPulse 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 monitoringEpidural analgesiaRegional anaesthesia preferred for caesarean section.Hourly vital signs- low threshold to start broad

spectrum antibioticsManagement of sickle cell Disease in pregnancy. RCOG2011

Post partum managementRisk of thrombo-embolism, painful crisisEarly ambulation, hydration,pain releif

(NSAIDS/pcm/ opoids)Prophylactic sucutaneous LMW heparin for 7 days

after vaginal delivery & 6 weeks following a caesarean section.

Aggressive treatment of suspected infectionCord blood – HPLCEncourage breast feeding Antithrombotic stockingBaby 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.

THALASSEMIASImbalance 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 distributionß -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 populationLeung 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 a-chains 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 ß-chain 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 majorNo 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 minorß-thalassemia trait/ minor-

Heterozygous- mildly reduced production of ß+ chains & thus, a mild excess of a globin chains which denature, causing damage to young red cells in the marrow (ineffective erythropoiesis) or decreased survival in the peripheral blood.

ß-thal intermedia mb homozygous for type 2 ß+ and type 3 ß+.

Mild anemia High Hemoglobin A2 levels

are classic. Hb F - mildly increased.

Folic acid 1mg/d to be supplemented

PBS- microcytic & hypochromic; often with associated erythrocytosis.

Basophilic stippling and reticulocytosis may help to distinguish the b-thal minor & fe def anemia(more common in thalassemia).

a -Thalassemia

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 screeningRBC 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 

contdWhen 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 diagnosisUnlike 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%, Fp-5.9%.

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 thalUSG- Not applicableAnalysis 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

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 & pre-eclampsia (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/dlProphylaxis for thromboemboism- no specific

regime. Acetylsalicylic acid antenatally for women who have undergone splenectomy & postpartum LMW heparin.

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.

Lam YH et al.Risk of neural tube defects in offspring of thalassaemia carriers in Hongcong Chinese. Prenat diag 2006.

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.

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.

Origa R et al. Pregnancy and beta thalassaemia: an Italian multicenter experience. Hematologica 2010; 95.

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 AIHAIgM Ab, optimally active at 4oCCauses - 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 hemolysisDetected 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 hemoglobinuriaClonal disorder of gene (PIG-A)

encoding GPI anchorProteins requiring GPI anchor to

attach to the RBC membrane are deficient - DAF, C8-bp, 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 urineMost 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 & PNHo Fertility is low, 15 pregnancies reported in 10 patients- 5 SA, 10 reached viability- good outcome

o ? Prophylactic washed RBC transfusionso Folic acid supplementation(3 mg/day)o Steroids to ↓hemolysis in acute episodeo BT may be neededo BMT, androgens – No role in pregnancyo Postpartum thrombotic events are common &

complete anticoagulation with warfarin is needed

Aplastic anemiao 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

these-ANC< 500/ dl, Platelet count< 20,000/dl& Anemia with Reticulocytes < 1% , with either bone marrow cellularity <25% or cellularity >50% with <30%

hematopoietic cells.

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.

Diagnosis & treatment of aquired aplastic anemia. Hematol oncol clin N Am 2009, 159-170.

Aplastic anemiao 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

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.

Pregnancy with aplastic anemia serious condition.

Causes1) Radiation2) Viruses- parvovirus; hepatitis (non-A, non-

B);EBV, HIV-1.3) Drugs- marrow suppressive chemotheraputic

agents -alkylating agents; antimetabolites-chloramphenicol; quinacrine; phenylbutazone;gold; hydantoin

4) Chemicals/Toxins- benzene; weed killers/insecticides; arsenic, glue sniffing

5) Immune disorders- SLE, thymoma6) Idiopathic

Harrison’s textbook of internal medicine, 17th ed

Aplastic anemia & pregnancyMaternalAntenatal complications- Preterm birth- 12.1% IUD- 16.7% Stillbirth- 15.1% Spontaneous miscarriage- 16.7%Intrapartum- Risk of hemorrhage during deliveryPostpartum- 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.

TreatmentSupportive therapy- Most important

Repeated blood transfusion to maintain Hb>8 mg/dlPlatelet transfusion yo maintain platelet count >

20,000/mcl.WBC transfusion can be considered in case of

fulminating infectionAntibiotic & barrier nursing.

Early stages -First line therapy - erythropoietin &GM-CSF.

If it fails - thymocyte gamma globulin & cyclosporineG-CSF & GM-CSF can be used in for

neutropenia/infectionBMT- 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.

ThrombocytopeniaPlatelet count below 1lakhAffects 10% of all pregnanciesPlatelet count decreases by 10% in normal

pregnanciesMostly physiologicMost 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)

ITPImmune ThrombocytopeniaDiagnosis of exclusionIncidence- 0.1-1 per 1000 pregnanciesMost 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.

ITPH/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 thrombocytopeniaOthers- Kft, DCT, TFT, autoimmune profile,

antiphospholipid antibodies.Bone marrow biopsy-indicated in minority of cases

only.*

Causes of maternal thrombocytopeniaIsolated 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 thrombocytopeniaCommonest cause of thrombocytopenia in healthy

pregnant womenFeatures-

o 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 counsellingAntenatal 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 ITP. Blood 2010; 115.

Management of ITP in pregnancyFirst 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 useLactating 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 pregnancyMode 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 avoidedManagement 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.

HemophiliaX-Linked recessiveHemophilia-A- Deficiency of factor viiiHemophilia-B- Deficiency of factor ixClassified as-

mild 6-30%. moderate 1-5%, severe<1% residual activity,

Prolonged APTTDiagnosis- 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 miscarriage(%)

Comments

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 unknown

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 monitoringPostpartum- risk of PPHNeonatal- 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