HEMATOLOGIC DISORDERS

IN PREGNANCY
Hematologic disorders in pregnancy

• Anemia
• Platelet disorders
• Thalassemia
 Anemia
• Non-pregnant women
- Hb < 12 g/dl
• Pregnant women
- greater expansion of plasma volume compared with the
increase in red cell volume
• Hb < 11 g/dl in 1st & 3rd trimester
• Hb < 10.5 g/dl in 2nd trimester
Hemoglobin Concentration
• Because of great plasma augmentation, hemoglobin
concentration and hematocrit decrease slightly during
pregnancy
 EFFECTS OF ANEMIA ON
PREGNANCY

• increased risk of preterm birth with midtrimester

anemia
• a low first-trimester hemoglobin concentration
increased the risk of
• low birthweight
• preterm birth
• small-for-gestational age infants
ANEMIA : CONTENTS
Most common causes of
1. Iron-deficiency anemia anemia during pregnancy
2. Anemia from acute blood loss and the puerperium
3. Anemia Associated with chronic disease
4. Megaloblastic anemia
5. Acquired hemolytic anemia
Iron-Deficiency Anemia
Iron-Deficiency Anemia
• Iron-deficiency anemia during pregnancy is the
consequence primarily of expansion of plasma volume
without normal expansion of maternal hemoglobin mass.
• the maternal need for iron averages close to 1000 mg.
• 300 mg is for the fetus and placenta
• 500 mg for maternal hemoglobin mass expansion
• 200 mg that is shed normally through the gut, urine, and skin.
Iron-Deficiency Anemia : Diagnosis
• Hypochromic microcytic (less prominent in pregnant
woman compare with nonpregnant woman)
• Serum ferritin < 10 to 15 mg/L confirm iron-deficiency
anemia
• Absent bone marrow iron stores by a bone marrow iron
smear
• Elevated of reticulocyte count after adequate iron therapy
Iron Deficiency Anemia
Treatment
Oral
• Ferrous fumarate , sulfate, or gluconate (200 mg of
elemental iron daily).
• Continue for 3 months after anemia has been
corrected.
Parenteral
• Ferrous sucrose (safer than iron-dextran)
Transfusion
• PRC or Whole Blood are not indicated unless
• Hypovolemia from blood loss
• Emergency operative on a severely anemic women
 Iron Deficiency Anemia
Iron supplement in pregnancy
• Normal pregnancy 35 mg/d
• Twin 60-100 mg/d
• IDA 200 mg/d
Ferrous sulfate : N/V
แนะนําให้ ทานก่อนนอน
Ferrous fumarate : more elemental iron
Normal pregnancy : 16 wk : Ferli-6 1x1 po pc
IDA : stat : Ferli-6 1x3 po pc
 Iron Supplement

การให้ธาตุเหล็กเสริม

Ferrous fumarate  element iron 33%

Ferrous sulfate  element iron 20%
Ferrous gluconate  element iron 10%

*ร่างกายดูดซึมเหล็กเพียง ~2-10%
 EXAMPLE
การให้ธาตุเหล็กเสริม
• The maternal need for iron averages ~7 mg/day
• FBC 1 tab have
Ferrous fumarate 200 mg
element iron 33%

66.67 mg
absorption 2-10%

6.67 mg
Anemia from Acute Blood Loss
Anemia from Acute Blood Loss
• Common in instances of abortion , ectopic pregnacy , and
hydatidiform mole
• Postpartum hemorrhage
 Acute Blood Loss
• In moderately anemic woman (defined by Hb ≤ 7 g/dL)
Who is
• hemodynamically stable
• able to ambulate without adverse symptoms
• not septic

*Blood transfusions are not indicated

Iron therapy is given for at least 3 months
Anemia associated with chronic
disease
Anemia Associated with Chronic Disease

• Renal insufficiency
• Suppuration
• Inflammatory Bowel disease
• Systemic lupus erythematous
• Granulomatous infections
• Malignant neoplasms
• Rheumatoid arthritis
Renal insufficiency

• Erythropoietin deficiency
• Renal impairment + disproportion of volume >> intensified

Treatment : Recombinant erythropoietion (when Hct ~20%)

Megaloblastic Anemia
Megaloblastic Anemia
Folic Acid Deficiency
• Found in woman who do not consume fresh green
leafy vegetables, legumes, or animal protein
• Excessive ethanol ingestion
• Early change :
• hypersegmented neutrophils
• macrocytic erythrocytes in PBS
 PBS : HYPERSEGMENTED NEUTROPHILS AND MACROCYTIC ERYTHROCYTES

http://www.pathologystudent.com/?p=1717
Megaloblastic Anemia

Folic Acid Deficiency

• The fetus and placenta extract folate from maternal
circulation so effectively that the fetus is not anemic
despite severe maternal anemia
• Folic acid requirement
• Nonpregnant women 50-100 µg/day
• During pregnancy 400 µg/day
Megaloblastic Anemia
I. Folic Acid Deficiency
• Treatment
• As little as 1 mg/day of folic acid orally. Reticulocyte count is
increased in 4-7 day after beginning of treatment.
Megaloblastic Anemia
I. Folic Acid Deficiency
• Prevention
• Diet sufficient in folic acid
• Recommended : all woman of childbearing age consume at least
400 µg/day
• Previously have had infants with NTD : daily 4 mg folic acid is given
prior to and throughout early pregnancy
Megaloblastic Anemia
II. Vitamin B12 Deficiency
• Rare
• Lack of intrinsic factor : partial or total gastric resection
• Other causes : Crohn disease, ileal resection, bacterial
overgrowth in the small bowel
• Total gastrectomy require :
• 1000 µg of vitamin B12 IM as monthly intervals
• Partial gastrectomy usually do not need therapy
• Unless treated with Vitamin B12 , infertility may be a
complication
Acquired Hemolytic Anemia
 Acquired Hemolytic Anemia

• Autoimmune Hemolytic Anemia

• Drug-Induced Hemolytic Anemia

• Pregnancy-Induced Hemolytic Anemia

• Paroxysmal Nocturnal Hemoglobinuria

• Severe Preeclampsia and Eclampsia

• Bacterial Toxin

• Hemolytic Anemia caused by Inherited Erythrocyte Defect

Acquired Hemolytic Anemia

Autoimmune Hemolytic Anemia (AIHA)

-Uncommon
- Coombs tests positive.
- Marked acceleration of hemolysis during
pregnancy.

Treatment
- Prednisone 1 mg/kg orally per day, or its
equivalent.
Acquired Hemolytic Anemia

DRUG-INDUCED HEMOLYTIC ANEMIA

- Mild hemolysis
- Resolves with drug withdrawal
- Drug-mediated immunological injury to red cells.
- Often related to a congenital erythrocyte enzymatic
defect, G6PD.
Acquired Hemolytic Anemia

PREGNANCY-INDUCED HEMOLYTIC ANEMIA

- Severe hemolysis in early pregnancy

- Resolves within months after delivery
- No evidence of an immune mechanism or
intraerythrocytic or extraerythrocytic defects.

Treatment
- Controlled by prednisone given until delivery.
Acquired Hemolytic Anemia

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

- Arises from one abnormal clone of cells, much like a

neoplasm
- Abnormal membrane proteins of the RBC >> lysis by
complement
- Complication : thrombosis
Acquired Hemolytic Anemia

SEVERE PREECLAMPSIA AND ECLAMPSIA

- Relatively common : Fragmentation or microangiopathic

hemolysis with thrombocytopenia

-Mild degrees are likely present in most cases of severe

disease and may be referred to as HELLP syndrome -
hemolysis, elevated liver enzymes, and low platelet
Platelet disorders
Platelet disorder
NORMAL PREGNANCY
• Normal pregnancy also involves changes in platelets
• Average plt count  slightly during pregnancy
• Within the normal range of 150,000 to 450,000/uL
•  platelet concentrations: hemodilution
•  platelet consumption  a greater proportion of
younger & larger platelets
Thrombocytopenia
• Platelet count below the lower limit of the normal
range (typically, <150,000/microL)
Cause
• Gestational thrombocytopenia (GT) – 75 percent
• Preeclampsia with severe features/HELLP syndrome
– 21 percent
• Immune thrombocytopenia (ITP) – 4 percent
 Gestational thrombocytopenia
• A benign, self-limited condition
• Characteristic
• Onset may be early in pregnancy, most common at
delivery
• Mild thrombocytopenia (≥80,000/microL, typically
100,000 to 150,000/microL)
• No increased bleeding or bruising
• No associated abnormalities on CBC
• No fetal or neonatal thrombocytopenia
• Resolve postpartum within 2-12 wk
Gestational thrombocytopenia
• Cause : may a result from hemodilution

• GT is a diagnosis of exclusion

• Accept GT only with followings

• Mild thrombocytopenia (>80,000/microL)
• No other associated finding on CBC or physical
examination
Preeclampsia with severe feature
HELLP syndrome
• Hemolysis
• Elevated Liver enzymes
• Low Platelet

• No need to have hypertension or proteinuria

• Lab investigations for features above to confirm the

diagnosis
Immune thrombocytopenic
purpura (ITP)
• An autoimmune condition in which antiplatelet
autoantibodies interfere with platelet production
and cause destruction of circulating platelets
• May occur during any trimester
• Severity is variable and may change during the
pregnancy
• Tests for antiplatelet antibodies are neither
sensitive nor specific
• The diagnosis is based only on the exclusion of
other causes
Immune thrombocytopenic
purpura (ITP)
• Acute ITP :
• Childhood disease that follows a viral infection
• Most cases resolve spontaneously, although perhaps 10
% become chronic

• Chronic ITP : Conversely, in adults

• Primary - young women and rarely resolves
spontaneously
• Secondary - appear in association with systemic lupus
erythematosus, lymphomas, leukemias, and a number
of systemic diseases
Immune thrombocytopenic
purpura (ITP)
• FETAL & NEONATAL EFFECTS
• Platelet-associated IgG antibodies cross the placenta
and may cause thrombocytopenia in the fetus-neonate
• Not a strong correlation between fetal and maternal
platelet counts
• Fetal death from intracranial hemorrhage occurs
occasionally (severely thrombocytopenic fetus is at
increased risk)
Immune thrombocytopenic
purpura (ITP)
• IMMUNE THROMBOCYTOPENIA AND PREGNANCY

• No evidence that pregnancy increases the risk of relapse

• Nor does it worsen thrombocytopenia in women with
active disease
• Hyperestrogenemia is also suggested as a cause
• Treatment is considered if plt count < 30,000-50,000/uL
(Prednisone)
Immune thrombocytopenic
purpura (ITP)
Treatment :
• Prednisone
• suppress the phagocytic activity of the splenic monocyte-
macrophage system
• platelet counts <30,000/uL or with significant bleeding at
higher levels are treated
• Prednisone, 1 to 2 mg/kg orally daily

• Intravenous immunoglobulin (IVIG)

• total dose of 2 g/kg over 2 to 5 days
Immune thrombocytopenic
purpura (ITP)
Treatment :
• Splenectomy
• For patients with
• no response to corticosteroid therapy in 2 to 3 weeks
• massive doses are needed to sustain remission
• frequent recurrences

• Immunosuppressive drugs
• Therapy is problematic for the 30 % of adults who do not
respond to corticosteroids or splenectomy
• Drugs including Azathioprine, Cyclophosphamide, and
Cyclosporine have been used with some success
Causes of thrombocytopenia in pregnancy
Gestational age Incidental finding of asymptomatic
thrombocytopenia
(platelet count 80,000 to 149,000/microL)
≤20 weeks •Most often GT
•ITP cannot be excluded, but no
evaluation or management would be
required
•Occurrence of other disorders not
different from non-pregnant patients
>20 weeks, at •Almost always GT
delivery, and •ITP cannot be excluded, but no
postpartum evaluation or management would be
required
•Occurrence of other disorders not
different from non-pregnant patients
https://www.uptodate.com/contents/thrombocytopenia-in-pregnancy
Platelet count <80,000/microL
•Not GT
•May be ITP
•Occurrence of other disorders not different
from non-pregnant patients
•Almost never GT
•If asymptomatic, ITP likely
•If hypertension, preeclampsia
•If symptoms of systemic illness as well as
MAHA:
• HELLP syndrome, if LFTs increased
• DIC, if coagulation abnormalities
present; suspect sepsis
• C-TMA, if AKI is severe
• TTP, if transient focal neurologic
abnormalities occur
•The frequency of these disorders increases with
gestation, with a peak occurrence at delivery and
the first postpartum week.
Inherited thrombocytopenia
• The Bernard-Soulier syndrome
• Lack of platelet membrane glycoprotein (GPIb/IX) →
defect in platelet plug formation & platelet-to-collagen
adhesion
• Maternal antibodies against fetal GPIb/IX antigen →
isoimmune fetal thrombocytopenia

• May-Hegglin anomaly
• Thrombocytopenia, giant platelets, and leukocyte
inclusions
• Infant was not affected
Don’t forget !!!
• To exclude pseudo thrombocytopenia first

Plt BT PT aPTT
↓ ↔ ↔ ↔
Platelet clumping
Prenatal Diagnosis in Thalassemia
 Thalassemia
Serious public health problem in Thailand ??

• Thalassemia
– Gene 30-40% (20 M)
– Disease 1 % (600,000)
• Couple at risk 5%
• Affected (disease) newborn 10,000/ Yr.
– Only Severe cases 5,000 / Yr.
RBC Consist of 4 globin chains and heme complex
Heme ----> Fe + porphyrin ----> ferroprotoporphyrin
Globin chain ----> polypeptides

Globin chain มีทงหมด

ั 6 ชนิด
 Alpha chain ( ) - Beta chain ()
 Gamma chain ( ) - Delta chain ()
 Epsilon chain ( ) - Zeta chain ()

Hemoglobin Synthesis: globin chain 2 สาย คือ alpha chain และ non
alpha chain

ADULT Hb: HbA 95-97%

HbA2 2-3%
HbF <1%
 Thalassemia
• Most common single gene defect
• An inherited autosomal recessive blood
disease.
• Reduced synthesis of Hb  anemia.
• Definitive cure by bone marrow
transplantation
 Thalassemia
• Autosomal recessive monogenic disorder
• Quantitative defect imbalance of globin
production

Alpha Thalassemia Beta Thalassemia

 Alpha Thalassemia
• Each chromosome 16 carries 2 loci, each loci carries 2 genes
• Underproduction or complete suppression of alpha-globin
chain
• Common molecular defected of alpha-thalassemia are
detection one or both of alpha globin gene
 Beta Thalassemia
• Each chromosome 11 carries 1 locus, each locus carries 2
genes control non-  globin chain (β, δ, γ)
• Underproduction or complete suppression of beta-globin
chain
 clinic อาจแบ่ งเป็ น 3 กลุ่ม

• Thalassemia minor
• Thalassemia intermediate
• Thalassemia major

“การดูแ ลรัก ษา Thalassemia ขึนอยู่ก ับ

ความรุน แรงของโรค (Phenotypic diagnosis)”
 Thalassemia Major
• Hemoglobin Bart’s hydrops fetalis
• Homozygous Beta-thalassemia
• Beta-thalassemia/Hemoglobin E disease
 Prevention
• Community and healthcare provider
education
• Heterozygote screening and couple at risk
detection
• Genetic counseling
• Prenatal diagnosis
• Termination of affected pregnancy
 Heterozygote screening and
couple at risk detection
• Hemoglobin Bart’s hydrops fetalis
α Thal 1trait + α Thal 1 trait

• Homozygous Beta-thalassemia
β Thal trait + β Thal trait

• Beta-thalassemia/Hemoglobin E disease
β Thal trait + Hb E
 Carrier screening

Screening Diagnosis

•Identify hypochromic •Hemoglobin

microcytic RBC electrophoresis
- Osmotic fragility test (OF) (Hb typing)
- Red cell indices
(MCV, MCH)
• PCR for alpha thal

•Identify Hb E genes
- DCIP
Screening
 Osmotic fragility test (OF)

 0.36% NSS
 Sensitivity
β-thal 90%,
α-thal 1 93%
β
•False positive
Normal
Iron deficiency 5%
Negative Positive
(Normal) Thalassemia trait /
Homozygous Hb E
 Osmotic fragility test (OF)

 Positive
β-thal trait
α-thal 1trait
Hb E trait (60-70%)

β •Negative
Normal
Hb E trait (30%)
Old blood
Negative Positive
(Normal) Thalassemia trait /
Homozygous Hb E
 Dichlorophenol indophenol
precipitation test
(DCIP)
DCIP 5 ml. + whole blood 30 µl.

Incubate 37 oc 1hr

Unstable hemoglobin Sensitivity 95 %

HbE
Positive Negative

Hb E
Hb H
Red cell indices : MCV, MCH
MCV < 80 fl
(mean corpuscular volume)

MCH < 27 pg
(mean corpuscular
hemoglobin)

Positive
β-thal trait
α-thal 1trait
Hb E trait (60-70%)
Diagnosis
 Hb A2 level

% A2
Normal <4
α-thal 1 trait <4
β-thal trait 4-8
Hb E trait β
10-30
β-thal/HbE disease 30-60
Homozygous Hb E > 60
Hb Electrophoresis

•Hb typing
•Quality
–A2A
–AH
–AE
–EF
–EE
•Quantity ??
–Cannot evaluate α Thal-trait
β0 , β +
DNA analysis

β
GAP-PCR for 0 -thalassaemia

β
GAP-PCR for 0 -thalassaemia
Negative for 7 common alpha thalassemia deletion
- Positive for alpha-thalassemia 1 (--SEA)
- Positive for alpha-thalassemia 1 (--THAI)
- Positive for alpha-thalassemia 1 (--MED)
- Positive for alpha-thalassemia 1 (--FIL)
- Positive for alpha-thalassemia 1 (-20.5 kb)
- Positive for alpha-thalassemia 2 (-3.7 kb)
- Positive for alpha-thalassemia 2 (-4.2 kb)
Summary
Partner risk for α 0-thal couple at risk for normal
homo β-thal, β-thal/E

DNA analysis couple

(PCR detection of --SEA ) thalassemia unlikely

Negative couple= α 0-thal trait

Thalassemia unlikely Genetic counseling and prenatal

diagnosis offered
 Genetic counseling
• Disease
- Type: b,E,a
- Genetic, Single-gene disorder , AR
- Disease (homozygous)
Vs. Carrier (heterozygote)
- Burden & Long-life blood pattern
- Treatment: Definite = Stem cell transplantation
• Risk assessment
• Option for Prenatal Diagnosis
• Treatment / Termination of pregnancy