Rh Disease and Neonatal Alloimmune Thrombocytopenia ... · Rh Disease and Neonatal Alloimmune Thrombocytopenia Purpura – What’s new? Kenneth J. Moise, Jr., M.D. Professor of Obstetrics

Rh Disease and Neonatal Alloimmune

Thrombocytopenia Purpura – What’s new?

Kenneth J. Moise, Jr., M.D. Professor of Obstetrics and Gynecology

Professor of Pediatric Surgery

The University of Texas Health Science Center

(UTHealth) Medical School at Houston

The Texas Fetal Center

Children’s Memorial Hermann Hospital

• Dr. Moise has received research support from

Sequenom, Inc. to evaluate the use of free fetal

DNA for fetal RHD typing in a multi-center

clinical trial

• Dr. Moise serves as a consultant to LabCorp,Inc.

• Dr. Moise receives royalty payments for

authorship of various chapters in UpToDate®

Disclaimer

• Evaluate new DNA technologies in the

management of the red cell alloimmunized

pregnancy and incorporate these methodologies

into clinical practice

• Describe current evidenced-based management

for the treatment of the pregnancy affected by

fetal/neonatal alloimmune thrombocytopenia

purpura

Objectives

DNA testing

Anti-D Anti-C Anti-c

+ - +

Anti-E Anti-e

- +

RED CELL ALLOIMMUNIZATION

Paternal Zygosity

Caucasian

Dce/dce (heterozygous RhD) – 90%

Dce/Dce (homozygous RhD) – 10%

Black

Dce/dce (heterozygous RhD) – 41%

Dce/Dce (homozygous RhD) – 59%


Paternal Zygosity


Paternal Zygosity

Buffy coat (maternal WBC’s =

DNA)

Maternal plasma (mixed

free maternal and fetal DNA)


Free Fetal DNA

New assay available from Sequenom®

3 male identifiers

92 SNP’s (6 must be different between mother and fetus)

Results

– RhD positive, male – valid result

– RhD negative, male – valid result

– RhD positive female – valid result

– Rh negative, female – need identifiers


Free Fetal DNA Testing

Rh D positive

result Valid

Rh D negative Reflex testing

Male fetus Female fetus

Reflex testing 92 SNP’s At least 6

different



Three collections from 120 patients

• Median: 12.4 weeks (10.6 – 13.9 wks)

• Median: 17.6 wks (16.0 – 20.9 wks)

• Median: 28.7 wks (27.9 – 33.9


Free Fetal DNA

Moise et al. Am J Obstet Gynecol 2012; 206:S315

Parameter First Trimester Second Trimester Third Trimester

Sensitivity (95% CI) 98.6% (0.93 - 1.0) 100% (0.95 - 1.0) 100% (0.95 - 1.0)

Specificity (95% CI) 100% (0.90 - 1.0) 96.8% (0.83 - 0.99) 94% (0.80 - 0.99)

Accuracy (95% CI) 99.1% (0.95 - 1.0) 99.1% (0.95 - 1.0) 98.1% (0.93 - 1.0)

Moise et al. Am J Obstet Gynecol 2012; 206:S315



38% of RhD negative patients will

carry an RhD negative fetus



Scenario #1 Non-invasive testing free fetal DNA testing used to

determine fetal RhD status

Antenatal Rhesus immune globulin held if RhD

negative fetus

Continue standard cord serology after birth to

determine need for Rh immune globulin



Szcepura et al. BMC Pregnancy and Childbirth 2011;11:5

Scenario #2 Non-invasive testing free fetal DNA testing used to

determine fetal RhD status

Antenatal Rhesus immune globulin held if RhD

negative fetus

No cord serology done after birth; forego Rhesus

immune globulin held if RhD negative fetus




Breakeven costs for non-invasive testing

Scenario #1: £18.43 ($29.17)

Scenario #2: £25.0 ($ 39.57)




Non-invasive sensitivity New cases (Scenario #1) New cases (Scenario #2)

94.8% 54 744

96.0% 42 573

98.0% 21 283

99.0% 10 141

99.9% 1 14



New cases of RhD alloimmunization in England and Wales


MCA

Doppler

< 15 °


MCA Doppler

Ruma et al. Am J Obstet Gynecol 2009;397.e1-397.e3


MCA Doppler

Abel et al. Am J Obstet 2003;189: 986-9 33 cm/sec

38 cm/sec

39 cm/sec

29 cm/sec


MCA Doppler

Swartz et al. Obstet Gynecol 2009;113:1255-6


MCA Doppler

515 MCA measurements in 66 fetuses

Intrauterine

Transfusion

Moderate Anemia Severe Anemia

1st IUT

↓

← 2nd IUT

← 3rd IUT

LOTUS trial

IUT’s between 1988 - 2008

291 children (85% participation)

Median age 8.2 yrs (range: 2 – 17 years)

Bayley Scales of Infant Development, Weschler

Preschool of Primary Scale of Intelligence,

Weschler Intelligence Scale for Intelligence


Long Term Follow-up

Lindenburg et al. Am J Obstet Gynecol 2012; 205:141.e1-8

Overall neurodevelopmental impairment – 4.8%

Cerebral palsy – 2.1%

– Dutch baseline: 0.7% @ 32 – 37 wks; 0.2% > 32

wks

Severe developmental delay – 3.1%

― Dutch baseline: 2.3%

Bilateral deafness – 1.0%


Long Term Follow-up



Long Term Follow-up


Parameter NDI No NDI OR

Mild hydrops 36% 18% 4.3 (1.2 – 15.3)

Severe hydrops 29% 6% 9.9 (2.4 – 40.5)

Hgb at first IUT 4.2 + 1.9 5.6 + 2.4 p =0.032

Z hemoglobin -8.1 -7.3 NS

No of IUT’s 4 (1-5) 3 (1-6) 1.7 per IUT

Gest Age < 32 wks 14% 1% 12.8 (2.1 - 79.5)

Severe neonatal

morbidity

43% 6% 13.1 (4.0 - 42.4)

Fetal/Neonatal

Alloimmune

Thrombocytopenia

Platelet Antibodies

• HPA-1a most common antigen in Caucasians

• Incidence: 1 in 1000 neonates

• Detection:

– 1st neonate born w/ thrombocytopenia

– Sister of patient with this history

• Rate of recurrence in subsequent sibs: 85 – 90%

Platelet Antigens

IIba III

IIbb vWF

fibronectin

fibrinogen

Ca 2+

S S

Platelet Antibodies

HPA-1a PlA1, Zwa GPIIIa 97.7%

HPA-1b PlA2, Zwb 26.5%

HPA-2a Kob GPIb 99.3%

HPA-2b Koa, Sibb 14.6%

HPA-3a Baka, Leka GPIIb 87.7%

HPA-3b Bakb 64.1%

HPA-4a Pena, Yuka GPIIIa 99.9%

HPA-4b Penb, Yukb 0.2%

HPA-5a Brb,Zavb GPIa 99.2%

HPA-5b Bra, Zava, Hca 20.6%

Platelet Antibodies

Specificity N Percent

HPA-1a 304 73.3

HPA-1a and 5b 11 2.7

HPA-5b 79 19.0

HPA-3a 8 1.9

HPA-2b 3

HPA-1b 3

HPA-5a 2

HPA-8b 1

HPA-12wb 1

HPA-13wb 1

Oea 1

HPA-4b 1

Fetal/Neonatal Disease

Intracranial hemorrhage • 10 - 20% of cases

• 75% of cases antenatal

• Mostly parenchymal

• Reported as early as 20 weeks

• Usually occurs after 30 weeks

• 100% recurrence if previous affected sibling

• Not predicted by maternal antibody levels

Evaluation

History of:

- Previous neonate with thrombocytopenia of unknown etiology

- Previous infant with platelet count < 50,000mm3 regardless of the

presumed etiology

- Previous fetus or neonate with intracranial hemorrhage of

uncertain etiology

Maternal thrombocytopenia

Reference laboratory testing:

- Maternal platelet antigen testing

- Paternal platelet antigen typing

- Maternal platelet HPA antibody

testing using sensitive assays

Evaluate for maternal anti-

platelet antibodies OR

history of autoimmune

thrombocytopenia

Yes

No

Evaluation

Incompatibility at HPA (1, 2,

3, 4, 5, 6, 9, 15)

Specific maternal anti-HPA

antibody to one of the

above present

Diagnosis of fetal

or neonatal

alloimmune

thrombocytopenia

No incompatibility at HPA

loci

Nonspecific or no anti-

platelet antibody testing

using sensitive assays

Incompatibility at HPA (1, 2,

3, 4, 5, 6, 9, 15)

Specific maternal anti-HPA

antibody to one of the

above NOT present

Test for maternal antibodies

at 30 weeks gestation

against father’s)

Detection of positive anti-

HPA antibodies that

react to paternal

platelets

Repeat maternal anti-HPA

antibody testing and

cross-match with

paternal platelets at 12,

24, and 32 wks EGA

No further evaluation

necessary

negative

negative

positive

Treatment

Previous infant w/ platelets

but no ICH

EGA 12 weeks:

IVIG (1 g/kg/wk)

EGA 20 weeks:

IVIG (1 g/kg/wk) and

predisone (0.5

mg/kg/day

OR

IVIG ( 2 g/kg/wk)

Previous fetus or infant with

ICH diagnosed > 28

weeks EGA

Previous fetus with ICH

diagnosed < 28 weeks

EGA

EGA 20 weeks:

IVIG to 3 g/kg/week

OR

add Prednisone

(0.5 mg/kgday)

EGA 20 weeks:

Add Prednisone

(1 mg/kg/day)

EGA 12 weeks:

IVIG (2 g/kg/wk)

EGA 32 weeks:


predisone (0.5

mg/kg/day)

EGA 28 weeks:


predisone (0.5

mg/kg/day)

Treatment (IVIF preparations)

Pacheco et al. Obstet Gynecol 2011;118:1157-63

• Side- effects

Flushing

Myalgia

Nausea

Hypotension

Fever and chills

Hemolytic anemia

Palmar desquamation

Headache

Treatment with IVIG

• Premedicate with acetominophen (1000 mg)

and diphenyhydramine (25-50 mg IV)

• Pre-hydrate; slow infusion

• Steroids

Decadron – 10- 20 mg orally

Decadron – 1 gram/ intravenously

Treatment with IVIG

• Give first dose in hospital

• Infusion rate: 1 gr/kg over 4 – 5 hours

• No more than 1 gr at one setting

• Give first dose in hospital setting

• Sequential doses with home therapy – IVIG

America

Treatment with IVIG

• Maternal platelephresis 3 days prior to planned

Csection

• Arrange donor infectious disease testing

May have positive marker from IVIG

FDA wavier to use designated platelets

• Do not wash (activates the platelets)

• Check cord platelet count usly

Delivery Considerations

Treatment

Previous infant w/ platelets

but no ICH

EGA 37 – 38 weeks:

• Csection after lung

maturity documented

• Vaginal delivery if

cordocentesis > 32 weeks

shows platelets > 100,0003

Previous fetus or infant with

ICH diagnosed > 28

weeks EGA

Previous fetus with ICH

diagnosed < 28 weeks

EGA

EGA 35 – 37 weeks:

• Csection after lung

maturity documented

• Vaginal delivery if

cordocentesis > 32 weeks

shows platelets > 100,0003

Which of the following is the most problematic

situation for determining the accuracy of free

fetal DNA testing for fetal RhD status?

a) RhD positive, male fetus

b) RhD negative, female fetus

c) RhD positive, female fetus

d) RhD negative, male fetus

Questions

A previous patient with NAIT experienced a

pregnancy complicated by a fetal intracranial

hemorrhage that was detected by ultrasound at 26

weeks gestation. The initial treatment for this

pregnancy would be to initiate:

a) 1 g/kg intravenous immune globulin weekly

b) 0.5 mg/kg/day oral Prednisone

c) 2 g/kg intravenous immune globulin weekly

d) 1 mg/kg/day oral Prednisone

Questions

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Rh Disease and Neonatal Alloimmune Thrombocytopenia ... · Rh Disease and Neonatal Alloimmune Thrombocytopenia Purpura – What’s new? Kenneth J. Moise, Jr., M.D. Professor of Obstetrics