AutoImmune Thrombocytopenic Purpura and pregnancy: the mother, the fetus and the newborn, from diagnosis to management
AITP and pregnancy
• AITP is a common hematological disorder, the patient’s platelets are destroyed by autoantibodies (Aab) • AITP may affect young women, association with pregnancy is not a rare event • Transplacental passage of maternal Aab could lead to fetal/neonatal thrombocytopenia
How to diagnose AITP when
thrombocytopenia is first discovered during pregnancy? What is the fetal/neonatal risk?
Platelet counts and pregnancy: a prospective study
• Physiological decrease of 11% of the platelet count whatever the initial platelet count • In 8,6% more pronounced drop up to 30.9% decrease of the platelet count leading to moderate thrombocytopenia prior to delivery • Maternal thrombocytopenia can be of immune origin [chronic autoimmune thrombocytopenic purpura (AITP)] and may result in fetal and neonatal thrombocytopenia.
Diagnosis strategies
• Excluding false thrombocytopenia • Time of onset • Clinical examination, past history, familial cases • Laboratory investigations: coagulation screen, liver function tests, lupus serology, platelet immunology
Thrombocytopenia
N<150.109/L
Yes
Past history
Past history
Thrombocytopenia in infancy
Thrombocytopenia during previous pregnancy
Was the infant thrombocytopenic?
Thrombocytopenic neonate
Diagnosis? Maternal Thrombocytopenia?
Thrombocytopenia N<150.109/L Yes Past history
No
Yes
Obstetrical disorders
Hypertensive disorder
Pre-eclampsia, HELLP syndrome…
No
Obstetrical disorders
congenital thrombocytopenias
No
Type 2B von Willebrand disease
HIV infection
Lupus
Autoimmune Thrombocytopenic purpura
Gestational thrombocytopenia
What are my own risks? Is there any fetal/neonatal risk?
Isolated thrombocytopenia first discovered during pregnancy
Gestational thrombocytopenia or AITP?
Gestational Autoimmunity thrombocytopenia – Thrombocytopenia – Mild highly variable thrombocytopenia – First trimester of – Late second or third pregnancy but could trimester of pregnancy occur later on – Absence of Aab – Fetal/neonatal risk and no predictive – No fetal risk parameter – Normal platelet count – Presence of Aab in the post-partum period
Gestational thrombocytopenia
Autoimmunity
Placental barrier
YY
Y
Y
“Gestational thrombocytopenia” revisited Assessment and follow-up of 50 thrombocytopenic pregnant women Asymptomatic autoimmunity in 48% Chronic thrombocytopenia in 55% Familial thrombocytopenia in 1 case Among women with mild thrombocytopenia 43% thrombocytopenic neonates 57% chronic thrombocytopenia
Our conclusion
• Gestational thrombocytopenia impossible to ascertain in primiparous women in the absence of previous platelet count • Necessary to follow-up the post-partum platelet counts within 6 months • Immunological studies should be performed to detect hidden autoimmunity • The platelet count of the newborn should be monitored during the 1st week of life when maternal thrombocytopenia first discovered during pregnancy
Laboratory diagnosis
Detection of antiplatelet autoantibodies
New techniques – “Capture” of the maternal antibody and identification of the target on the platelet (MAIPA-test) – These techniques are not routinely done Results – Autoantibodies the hallmark of autoimmunity, not found in gestational thrombocytopenia Our approach – Search for Aab when isolated thrombocytopenia discovered, and if negative results, at delivery and in the post-partum period
The fetus and The newborn
The fetal/neonatal thrombocytopenia
The fetal/neonatal thrombocytopenia is unpredictable*, no predictive maternal parameter 30-40% of infants born to mothers with AITP will be thrombocytopenic 10-15% of infants will be severely thrombocytopenic (<50.109/L) Only 0-3% of infants will suffer intracranial hemorrhage Neonatal thrombocytopenia usually worsens during first days of life, nadir day 3 to 5 lasts from 10 to 60 days *unless prior thrombocytopenic sibling
Prospective study
• Fetal thrombocytopenia observed as early as 20 weeks of gestation • No spontaneous correction • Cannot be prevented or reversed by maternal therapy such as corticoids or intravenous immunoglobulins
The newborn
Once upon a time….
Marie Charlotte : 1988, P1G1
• • • • Full term infant, vaginal delivery, normal Apgar score. Petechiae : 8x109pl./L, normal maternal platelet count Neurological symptoms and ICH IVIgGx2, exchange transfusion, maternal platelet transfusions were without any effect. • Thrombocytopenia resolved spontaneously at D15 • Hydrocephaly, neurological derivation, death at D22. Maternal platelet life span study: compensated thrombocytolysis
Marie Charlotte : 1989 P2G2
• fetal blood sampling by cordocentesis (FBS) 35 weeks gestation : 7x109pl./L • Maternal therapy: IvIgG 0.5g/kg/2days during 2 weeks • C-section, full term baby: Agathe • Petechiae 5x109 pl. /L. • Thrombocytopenia lasted 45 days despite IVIgG • Specific maternal Aab (antiGPIb-IX)
M a rga ux , born on june 1 2 ,1 9 9 1 , C -s e c tion, no F BS
p latelets (10 /L )
300 250 200 150 100 50 0
IvIg G 1 g k g /d
9
IvIgG 0.5g/kg 2d Day 54
7/8
12/6
26/6
10/7
24/7
D AYS
21/8
4/9
E d g a r, b o rn o n ju ly 1 7 ,1 9 9 5 (C -s e c tio n )
140 120 100 80 60 40 20 0
pla telets (x10 /L)
9
IV IgG
1g /K g
/7
/7
/7
/8
17
24
31
7/
14
D a ys
21
/8
8
Mrs R.H.(1) • Born in 1951 • 1971 first pregnancy: a thrombocytopenic boy (20.109/L) with petechiae. Thrombocytopenia resolved at D+20. Normal maternal platelet count. Anti HLA ab found in the maternal sera • 1988 second pregnancy: FBS at 23 and 37 weeks of gestation: 195 and 212.109/L. Vaginal delivery, D+2: petechiae +23.109/L.Platelet tfs and IvIgG (0.5G/Kg/d 4 days), D+7 normal pl.count
Mrs R.H.(2) • 1990 third pregnancy, FBS at 23 and 32 weekgestation, normal pl.count. Birth, at 32 weeks of gestation, pl.count 157.109/L. 12 hours later petechiae, umbilical hemorrhage and severe thrombocytopenia 17.109/L. Maternal pl.tfs, Exchange Tfs, IvIgG were ineffective, the thrombocytopenia lasted 11 days. • Specific maternal Aab (anti GPIb-IX) • Maternal platelet life span study: compensated thrombocytolysis
“Hidden maternal autoimmunity”(1)
• 11 mothers normal platelet counts, no previous immunological or platelet disorders • 17 newborns with severe and transient thrombocytopenia. The fetal/neonatal thrombocytopenia differ in severity and duration • Specific Aab in 10/11 mothers and 3/4 infants • Compensated thrombocytolysis and/or hypersplenism found in 10/11 women
DIAGNOSIS: mild AITP
“Hidden maternal autoimmunity”(2)
• Increase susceptibility of fetal/neonatal platelet to the anti GPIb-IX antibody? (fetal platelet conformation?) • However: pregnant women with anti GPIbIX without thrombocytopenic infant (8% of normal post-partum control study).Natural autoantibodies (Aab)? • Are these Aab different from those found in “hidden autoimmunity” and overt AITP ? • What is the predictive value of these antibodies for the fetal or neonatal risk ?
When to perform laboratory testing for maternal autoimmunity?
• When fetal or neonatal thrombocytopenia is unexpected • When intracranial hemorrhage is diagnosed by ultrasound • Autoimmunity should be considered among other etiological factors in unexplained in utero death, or miscarriages • Well-versed laboratory required
Management
Optimum management of pregnant women with AITP requires close collaboration between the physician, obstetrician and neonatologist
During pregnancy (1)
Maternal risk – Low, most of the pregnant women without any therapy – However, therapy could be required if there is a thrombocytopenia below 50.109/L , or hemorrhagic syndromes (easy bruising, petechiae) – Epidural anesthesia is not allowed if the platelet count is <80.109/L
During pregnancy (2)
Maternal therapy Corticosteroids (CS) 1mg/kg/d (prepregnancy weight), • response to therapy 3 days to 2 weeks, • then low doses to maintain a safe platelet count. • Prednisone@ is safe for the fetus • however adverse effect have been reported for the mother such as hypertensive disorder, gestational diabetes….
During pregnancy (3)
Maternal therapy Intravenous immunoglobulins (IvIgG) 1g/kg ( prepregnancy weight), • response 24 to 48h, maximum efficacy à D4. • IvIgG can be given in the pre-delivery period. In case of failure CS can be associated with IvIgG Splenectomy rarely done (2nd trimester)
Delivery (1)
Conservative approach
No more assessment of the fetal platelet
count Fetal scalp blood sampling after membrane rupture and partial cervix dilatation falsely low platelet counts Fetal blood sampling: complication rate 0-5%, fetal ICH 0-3% of cases, no effect of antenatal therapy not recommended in that setting, more risks than potential clinical benefits.
Delivery (2)
Way of delivery Controversies still exist concerning the best way of delivery to avoid intracerebral hemorrhages for severely thrombocytopenic fetuses C-section advocated to avoid ICH Vaginal delivery been suggested to bear a higher risk No prospective study showing Csection more effective
Delivery (3)
Our approach Vaginal delivery In case of obstetrical complications and suspicion of severe fetal thrombocytopenia, C-section
The newborn
Close monitoring of the platelet counts at birth, 24 hours later, Days 3 and 5 In case of severe thrombocytopenia or hemorrhagic syndromes: IvIgG 1g/kg/d Breast-feeding is not discouraged
In conclusion
• AITP common hematological disorder and association with pregnancy not a rare event • Distinction between AITP and gestational thrombocytopenia difficult when thrombocytopenia first discovered during pregnancy • Serious maternal risks uncommon
• Severe fetal/neonatal thrombocytopenia with ICH only in 0-3% of cases, no
predictive maternal parameter. Close monitoring necessary. • More conservative management
Bicètre Hospital • Pr Gil Tchernia • Dr Marie Dreyfus •Dr Nadine Ajzenberg •Dr Jeanine Yvart
Puericulture Institute • Dr Fernand Daffos • Pr François Forestier
The Immune Working Group • Dr Elisabeth Verdy • Pr Serge Uzan • And colleagues from the AP-HP National Institute of Blood Transfusion • Marie-Christine Morel-Kopp • Dr Cécile Kaplan