Reproductive Issues in ITP

Terry Gernsheimer, MD6 July 2018

Issues Specific to Women with Thrombocytopenia

• Menstrual bleeding• Fertility• Pregnancy• Breast feeding

Menstrual Bleeding and ITP

• Menses may be abnormally heavy, prolonged– Antifibrinolytic therapy

• Tranexamic acid 650 – 1300mg daily for 3-5 days• Oral contraceptives• IUDs• Progesterone implants

• Irregularity due to medications

Fertility• Multiple medications may affect fertility

– Corticosteroids– Cyclophosphamide

• Pregnancy should be avoided– Rituximab within 6 months– Mycophenolate– TPO receptor agonists– Danazol

Platelet count at term in healthy pregnancy

Boehlen F et al. Obstet Gynecol 2000;95:29–33

20

15

10

5

0

Wom

en (%

)

Platelet count (G/L)

500

Control women

Pregnant women

25

Mean platelet counts: pregnancy vs controls

Characteristic Pregnant(n=6770)Controls (n=287) p

Mean age (years)29.8

(15–47)29.6

(18–47)0.68

Platelet count (x 109/L)213

(116–346)248

(164–362)0.001

2.5th percentile 116 164 0.00197.5th percentile 346 362 0.33

Pregnancy-associated thrombocytopenia

• Isolated Thrombocytopenia– Incidental (Gestational)– Immune (ITP)– Drug-induced

HIT– Congenital– Type IIb vWD

• Systemic Disorders- Preeclampsia- HELLP syndrome- Acute fatty liver - Thrombotic

microangiopathies- SLE / Antiphospholipid

antibodies- DIC- Viral infection - Nutritional deficiencies- Hypersplenism- Bone marrow dysfunction

Causes of maternal thrombocytopenia

Data from Burrows RF, Kelton JG, N Engl J Med 1993; 329:1463-1466

74%

4% 21%1%

OtherIncidentalImmuneHypertensive

Immune Thrombocytopenia (ITP) in Pregnancy

Incidence: 1 in 1,000 to 1 in 10,000 pregnancies

Most common cause of thrombocytopenia in 1st trimester

Symptoms similar to ITP in non-pregnant patients

31% require treatment

Incidence of neonatal thrombocytopenia ~20%– 4% severe

1. Gill KK & Kelton JG. Semin Hematol 2000;37:275–289

How do we diagnose ITP in pregnancy?

29%

38%

33%

27%

46%

27%37%

38%

25%

Platelet Count

• As in the non-pregnant setting, diagnostic tests are used to exclude alternative causes of thrombocytopenia

• History• Physical examination• Exclusion of other causes:

– Timing – often noted in first and second trimester– Severity– Presence of other hematologic abnormalities– Hypertension– Infection– Laboratory abnormalities

Diagnosis of ITP in pregnancy

Gernsheimer T , James A, Stasi R. Prepublished online Blood. November 13, 2012

Evaluation of thrombocytopenia in pregnancy

Review blood smear PseudothrombocytopeniaLarge plateletsFragments

Clinical History &Physical Exam

History of thrombocytopeniaBleeding historyHypertension

Laboratory evaluation Coagulation Testing, vWFThyroid testingLiver Function TestsVirus – HIV, HCV, H PyloriANA, Lupus anticoagulant, ACLA

• Provan D et al. Blood 2010;115:168–186; Gernsheimer T , James A, Stasi R. Prepublished online Blood. November 13, 2012

Reese JA et al. N Engl J Med 2018;379:32-43.

Mean platelet counts during gestation

At what platelet count should a pregnant patient with thrombocytopenia start to receive treatment for ITP?

Which drugs can be safely used during pregnancy?

• What is considered a “safe” platelet count for epidural anesthesia?

What should mode of delivery be based on?

Case: Immune Thrombocytopenia (ITP) in Pregnancy

• Diagnosis of ITP at age 10 with petechiae• Corticosteroids for platelet fall with URIs• Pregnancy #1, 2007-2008

• Platelets 50-60,000/µL first trimester• Second trimester 40-50,000/µL

• Prednisone 20mg daily 108,000

• She requests an epidural for delivery• Platelet count at delivery 50,000/µL

• Indications for therapy– First and second trimesters

• Symptomatic• Platelet count 20–30,000x109/L• Procedures

• Monitor more frequently in third trimester

• Therapy based on risk of maternal haemorrhage

• First-line therapy– Corticosteroids– IVIg

• Combine first-line therapies in refractory patients

Management of ITP in pregnancy (1)

Gernsheimer T , James A, Stasi R. Prepublished online November 13, 2012; Provan D et al. Blood 2010;115:168–186

Second-line therapies

• Splenectomy– Rarely performed in pregnancy, but is best performed in the

second trimester

• Azathioprine

• High dose steroids +IVIg or azathioprine

• Cyclosporine

Should not be used• Immunosuppressive drugs (other than azathioprine, cyclosporine)• Vincristine, danazol, rituximab***• TPO receptor agonists***

Management of ITP in pregnancy (2)

Gernsheimer T , James A, Stasi R. Prepublished online November 13, 2012 Provan D et al. Blood 2010;115:168–86TPO, thrombopoietin; HDMP, high dose methylprednisolone

***TPOr and TPO Agonists in Pregnancy

• 6 reported cases with romiplostim• Eltrombopag has not been reported• Recombinant human TPO

– China 31 patients treated• 23/31 patients responded (74%)• 10 complete response

• In all reports patients and newborns without adverse events

• Mode of delivery determined by obstetric indications– Most neonatal hemorrhage occurs at 24–48 hrs – Fetal platelet count measurement not recommended– Avoid procedures with increased fetal bleeding risk

• Epidural anaesthesia– Risk of spinal hematoma unknown– Platelets of 75–100,000/µL generally recommended– Other tests for risks of bleeding, history

Management of delivery

Provan D et al. Blood 2010;115:168–186; Gernsheimer T , James A, Stasi R. Prepublished online November 13, 2012Douglas MJ. In: Evidence Based Obstetric Anesthesia. Massachusetts: Blackwell publishing; 2005; Hunt BJ. Int J Obstet Anesth 2005:14:324–25

Cesarean section in ITP and outcome

Cook et al. (Obstet Gynecol,1991) 474 cases of infants born to mothers with ITP No differences in incidence of ICH or other bleeding

complications between infants delivered vaginally or by C-section

Burrows and Kelton (Obstet Gynecol Surg, 1993) 288 infants born to mothers with ITP 10% had platelet counts

Case continued• The patient’s newborn son had petechiae on his

forehead at 1 day of age.• His platelet count was 50,000/µL, falling to

17,000 several days later.• He was treated with IVIg and transfused platelets

with an increase in the count to 127,000/µL. 3 days later the platelet count was 47,000.

• He required repeated doses of IVIg 3 additional times before the platelet count stabilized at 2 months of age.

• The patient asks what the chance is her next child will also be affected.

Incidence of Severe Neonatal Thrombocytopenia in ITP

Case Series

Fetal Platelet Counts

No. of pregnancies

/births

• Severe neonatal thrombocytopenia –

Relationship of maternal and infant platelet count at delivery

Hachisuga S, et al. Blood Research. 2014; 49(4): 259-64

Neonatal platelet count and maternal therapy

Sun D et al. Blood 2016;128:1329-35

Koyama S, et al. Am J Hematol. 87:15-21, 2012

Correlation of sibling platelet counts at birth and at nadir

P = 0.001 P < 0.0001

ITP in Pregnancy: Summary• ITP is an uncommon disorder in pregnancy

• Management of ITP in a pregnant patient does not differ substantially from that in a non-pregnant patient

• Up to 20% of the offspring of patients with ITP may be thrombocytopenic

• Incidence of severe neonatal thrombocytopenia ~4%,

• Platelet nadir may occur days after birth and last weeks

• Neonatal ICH is rare

• History of ITP or ITP in pregnancy is not a contraindication to future pregnancy

• A history of ITP or ITP during pregnancy is not a contraindication to future pregnancy

• …but history does repeat itself!

Reproductive Issues in ITPIssues Specific to Women with ThrombocytopeniaMenstrual Bleeding and ITPFertilityPlatelet count at term in healthy pregnancyMean platelet counts: pregnancy vs controlsPregnancy-associated thrombocytopeniaCauses of maternal thrombocytopeniaImmune Thrombocytopenia (ITP) in PregnancySlide Number 10Platelet Count and CauseDiagnosis of ITP in pregnancyEvaluation of thrombocytopenia �in pregnancyReese JA et al. N Engl J Med 2018;379:32-43.Slide Number 15Slide Number 16Slide Number 17Slide Number 18Case: Immune Thrombocytopenia (ITP) in PregnancyManagement of ITP in pregnancy (1)Management of ITP in pregnancy (2)***TPOr and TPO Agonists in PregnancyManagement of deliveryCesarean section in ITP and outcomeCase continuedIncidence of Severe Neonatal Thrombocytopenia in ITPManagement of the NeonateRelationship of maternal and infant platelet count at deliverySlide Number 29Slide Number 30ITP in Pregnancy: SummarySlide Number 32