1. Hematologic Disease in Pregnancy
Raymond Powrie, MD, FRCP(C) FACP
Professor of Medicine and Obstetrics and Gynecology
Alpert Medical School at Brown University
Interim Chief of Medicine
Women and Infants Hospital of Rhode Island
Chief Medical Quality Officer
Care New England Healthcare System

2. Incidence of Common Hematologic Problems in Pregnancy
Iron Deficiency Anemia ~10%
B12 Deficiency 5%
Folate Deficiency 5%
Hemoglobinopathies and thalassemias 5%
Sickle Cell 4%
Alpha thalassemia 0.8-5%
Beta thalassemia %
Thrombocytopenia
< %
< % %
Von Willebrand’s 1%
Hemophilia

3. Anemia

4. Anemia Defined <10.5 g/dL
Hgb < 6 g/dL has clear fetal consequences

5. Anemia MCV Possible Etiologies Initial Investigation Low
Iron deficiency
Thalassemia
Hgb-opathies
Serum Ferritin
Low: Iron deficiency
Normal: Hgb electrophoresis
Normal
Anemia of chronic disease
Acute blood loss
Hemolysis
Reticulocyte count
Normal: Medical history ferritin, TSH, Creatinine
High: Smear, LDH, Bili, haptoglobin
High
B12/Folate deficiencies
Alcohol/Liver Disease
Reticulocytosis
Normal: B12, serum and RBC folate levels, AST check alcohol and medication history (AED, AZT)

6. Iron Deficiency Anemia
Evaluate for GI blood loss
Ferrous sulfate 325 mg two to three times a day
Supplement with vitamin C or red meat to increase absorption
Do not take with calcium, tea, coffee or wine
Expect a 0.8 g/dL/week with iron supplementation after a few weeks
Rarely a need for parenteral iron

7. Thalassemia Hemoglobinopathies
5% of the world’s population
Mediterranean, Africa, Indian Subcontinent, SE Asia, the Pacific

9. Thalassemias
Hemoglobin chains NOT made so there is anemia
Hemoglobinapathies
Hemoglobin chains made with flaws so there is anemia

10. Thalassemia

11. Thalassemia/Hgb-opathy
MCV <27 pg
Hgb Electrophoresis
Hb H Bodies
HbA2 >3.5%
A-Thal
B-Thal
Abnormal Hb on electrophoresis
Potentially clinically significant Hb S Hb E Hb C Hb Lepore

12. Hemoglobin Structure Two Alpha globin chains from 4 genes
Two Beta globin chains from 2 genes
Thalassemia classified by
Phenotype: Clinical severity
Genotype: number of gene abnormalities
Fetuses have alternatives to Beta chains but not to alpha chain deletions

13. Alpha thalassemia Number of absent/ineffective Alpha genes
Variant Hemoglobin
Clinical manifestation
1 gene mutation
None
Clinically silent mild red cell microcytosis
2 gene deletions
Thalassemia trait: Normal or Mild microcytic anemia
3 gene deletions
Hgb H 8-10%
Hb A2 1-2%
Hb F 1-3%
Chronic anemia
Hb 7-10 g/dL
MCV fL
MCH pg
4 gene deletions
Hgb Barts
Hydrops fetalis
Lethal

14. Beta Thalassemia Gene mutation/deletion Variant hemoglobin
Clinical Manifestation
One of the two beta genes
Hgb A2>3.5%
“trait” : mild microcytic, hypochromic anemia
Both of the two beta genes
Hb A2 and F
“major”: severe anemia Hb3-7 MCV and NCH pg

15. Sickle Cell Disease

16. Sickle Cell Trait/Disease
Increased pregnancy complications
Miscarriage: 36% versus 10%
IUFD: 6% versus 1%
Preeclampsia: 15-20% versus 5%

17. Sickle Cell Disease Prevention of Crises Continuous good hydration
Folate 1 mg daily
No role for prophylactic blood transfusions

18. Sickle Disease Treatment of Crises
Aggressive pain control with narcotics
Hydration
Oxygen
Continued folate
Careful search for and treatment of any infection
Transfusion to achieve at least 50% normal hemoglobin if severe
Chest crises have a significant mortality associated with them and should be taken very seriously

19. Combinations Hb E 20-60% of Southeast Asians carry this gene
Hb C 3% of Africans
Hb S 12% of Africans
Hb Lepore
Significant when combined with thalassemia traits or found in homozygous states

20. Thrombocytopenia

21. Thrombocytopenia <150 X 109 /L abnormal
< X 109 /L epidural precluded
<50 X 109 /L Increased risk of surgical bleeding
<10-20 X 109 /L increased risk of spontaneous bleeding

22. Etiology Etiology Diseases Tests Decrease production
After viral infection (Rubella, mumps, varicella, parvovirus, Hip and EBV)
Chemotherapy or radiation therapy
VitB12 and Folic acid deficiency
Complete blood count with MCV
Other tests based on history and physical
Increased destruction
ITP
SLE
DIC, TTP,
APL syndrome, HELLP
Drugs: Heparin, Quinine, Valproic acid
HIV cause direct destruction of megakaryocytes
HIV
Sequestration
Hypersplenism
Examine for splenomegaly
Factitious
Platelet clumping or thrombosis
Collect CBC with citrated tube

23. Gestational Thrombocytopenia
The frequency in the largest series of consecutive women admitted for delivery is 5% (Burrows RF, Kelton JG, N Engl J med 1993; 329:1263)
Defined by the following five criteria:
Mild and asymptomatic thrombocytopenia, More than
No past history of thrombocytopenia (except previous pregnancy)
Occurrence during late gestation
No association with fetal thrombocytopenia
Spontaneous resolution after delivery

24. Immune (Idiopathic) Thrombocytopenia
Common acquired bleeding disorder
Two criteria required for the diagnosis:
1. Isolated thrombocytopenia with other wise normal CBC
2. Absence of clinically associated conditions ( e.g. SLE, APL, CLL)
Incidence is 50-60/million/year
Women of childbearing age accounts for the majority of the cases
It is not uncommon therefore for a woman to enter pregnancy with a known diagnosis of ITP or to develop de novo ITP during pregnancy itself

25. Clinical Manifestations
Marked variability in the clinical presentation
Onset usually insidious but can be acute and abrupt
Usually asymptomatic
Bleeding usually muco-cutaneous
Petichiae, purpura, and easy bruising (Expected))
Epistaxis, gingival bleeding , and menorrhagia Common)
GI bleeding and gross hematuria( Rare)
Intracranial hemorrhage ( Fatal, Very rare)

26. Diagnosis
Diagnostic approach to ITP in a is the same as in non-pregnant patients.
No “gold standard” test to diagnose ITP.
Diagnosis is reached after exclusion of other causes using clinical history and exam, CBC and peripheral blood smear.
Additional lab tests to consider include testing for autoimmune disorders, and exclusion of HIV Antiplatelet
Antibody testing is not recommended by American Society of Hematology

27. Effect Of Pregnancy On ITP
ITP accounts for 3-4% of the cases of thrombocytopenia detected in pregnancy
Pregnancy does not per se alter the natural course of ITP or increase the risk of relapse in women with previously diagnosed ITP

28. Effect Of ITP On Pregnancy
Thrombocytopenia in the infant can occur due to passive diffusion of autoimmune antibodies across the placenta
In one review of 10 studies of 600 pregnancies in 469 women with known ITP reported neonatal thrombocytopenia:
< in 28%
< in 11%
ICH in 1.2%
Maternal platelet count at delivery is not predictive of neonatal platelet
The risk of spontaneous bleeding in pregnant women is low

29. Treatment of ITP
The goal for treatment of ITP is to provide a safe platelet count to prevent major bleeding, rather than returning the platelet count to normal
Treatment is considered if the platelet count is <30-50,000.
Some will treat for platelet counts <80,000 to allow regional anesthesia

30. Treatment in pregnancy
Prednisone is First line
1 mg/kg/day for 7-10 days and then gradually taper taper to keep platelet above the desired threshold
The lowest possible dose should be aimed for < 10 mg daily, most likely throughout the pregnancy
Can increase the risk of GDM, HTN, maternal infection and preterm delivery but no fetal effect

31. Treatment (Continued)
IVIG (gamma globulin)
May be considered first line in third trimester
1 g/kg ( pre pregnancy wt) daily for 2 days
Provides effective ( 80% )but temporary improvement in platelet count (usually last for 2-4 weeks)
Indicated in women with moderate or severe bleeding symptoms or whose platelet < 10,000
Can be repeated but expensive and time consuming to administer
No effect on fetal platelet count

32. Treatment (Continued)
Azathioprine
Is a steroid-sparing agent
used in pregnancy in conjunction with corticosteroids in women with refractory ITP
Splenectomy
Laparoscopic splenectomy has been safely carried out mainly in second trimester

33. Treatment (Continued)
High doses Methylpredisone 1 gm IV
Dexamethasone 40 g daily for 4 days
can cross the placenta with fetal effect
Rituximab Monoclonal antibody therapy
used with caution in pregnancy as it crosses the placenta and can cause temporary suppression of fetal B lymphocytes and unclear long term effect on development of fetal immune system
Platelet transfusion
for severe, symptomatic thrombocytopenia

34. Delivery
Vaginal delivery preferable but mode of delivery should be determined by obstetric indications
Neuroaxial anesthesia:
Although the precise platelet count needed to safely perform neuroaxial analgesia is unknown, a platelet count variously given as > or > is considered safe for epidural/spinal anesthesia/analgesia if coagulation is otherwise normal.

35. von Willebrand’s Disease VWD
Most common inherited bleeding disorder: 1% of population
Quantitative or qualitative deficiency in von Willebrand factor (VWF)
VWF has two roles
Helps platelets stick to each other, to damaged tissue and to fibrinogen
Carrier protein for FACTOR VIII that keeps FACTOR VIII from being broken down prematurely

36. VWD VWD type Type 1 Not enough VWF made Type 2 Faulty VWF made
Type 2B has VWF that works BETTER than the other kind and can cause thrombosis
Type 3
No VWF made

37. Bleeding Disorders History Easy bruising especially without injury
Bleeding following dental work or surgery
Gingival bleeding
Menorrhagia
Lab
CBC
aPTT, INR
PFA-100
Bleeding time

38. Von Willebrand’s Disease

39. Testing for VWD VWF antigen How much VWF is there? Factor VIII antigen
Does the VWF do its job at protecting Factor VIII?
VWF ristocetin cofactor activity (VWF:RCoA)
Does the VWF do its job at bringing platelets together to do their work?

40. Pregnancy VWF and factor VIII levels go up in pregnancy
Patients generally fine if Ristocetin cofactor activity levels >50 IU/dL
Patients with type 2 VWD may have worsened thrombocytopenia in pregnancy

41. Treatment in Pregnancy
Review prior tests and confirm diagnosis
VWD testing at booking and at 34 weeks
If >50 IU/L:
no treatment
If <50 IU/L
If Type 1 or 2A
PRN DDAVP 0.3 mcg/kg IV/SQ postpartum for vaginal delivery
Preventive DDAVP 0.3 mcg/kg IV/SQ prior to CS
If Type 2B 2N 2 M or type 3… give intermediate purity FVIII concentrate IU/kg

42. Treatment in Pregnancy
Inherited illness but generally high levels of FVIII and VWF in newborn

43. Hemophilia

44. Hemophilia Treatment Hemophilia A Disease and Inheritance Deficiency
Pregnancy Effects
Treatment
Hemophilia A
XLR
Factor VIII
Increase in
F VIII
DDAVP or FVIII concentrate to get levels >50 IU/dL for any procedure
Male fetuses should not get vacuum extraction or IM injections prior to testing
Hemophilia B
Factor IX
No change in
F IX
Recombinant F IX to get levels > 50 IU/dL for any procedure
Hemophilia A

45. Hemophilias Deficiency and Inheritance Pregnancy concerns Treatment
Factor XI AR
Bleeding usually only with trauma or surgery
FFP or Factor XI concentrate to maintain F IX levels > 50 IU/dL prior to procedure and for 4/7 days after a vaginal delivery / CS
Factor VII
Levels increase in pregnancy
FFP or F VII concentrates to achieve ? goal
Factor XIII
High risk of Intracranial hemorrhage
High miscarriage and PPH rate
FFP or F XIII concentrates to achieve ? goal