Immune thrombocytopenic purpura (ITP) occurs commonly in women of child-bearing age (Fredriksen & Schmidt, 1999). The management of ITP during pregnancy must take into account certain features: (1) a platelet count of 50 × 109/l is recommended for delivery and a count ≥ 80 × 109/l is usually required for epidural anaesthesia (Bromage, 1993; British Committee for Standards in Hematology General Haematology Task Force, 2003); and (2) its management primarily involves steroids and intravenous immunoglobulin (IVIG) (Gill & Kelton, 2000). Anti-Rh (anti-D) has been used for 40 years, including antepartum dosing, to prevent rhesus alloimmunization during pregnancy in Rh(D)-negative women (Moise, 2001). In Rh(D)-positive patients, with ITP and at doses 10- to 20-fold higher than those used for the prophylaxis of Rh disease, anti-D provides a significant platelet increase in > 70% of cases (Newman et al, 2001). At such doses, post-infusion reactions (i.e. fever, chills, headache) are common, and anti-D can lead to some degree of haemolysis (Scaradavou et al, 1997). Compared with IVIG, anti-D has the advantages of being less expensive, having a much shorter infusion time and being derived from a smaller donor pool (Blanchette & Carcao, 1998). Its use in ITP during pregnancy has been limited by the fear of fetal/neonatal haemolysis and the lack of data describing its efficacy in pregnant women. This prospective pilot study was performed to investigate the safety and efficacy of anti-D in pregnant women with ITP.
Summary. This pilot study assessed the safety and efficacy of intravenous anti-D in eight Rh(D)-positive women with immune thrombocytopenic purpura (ITP) during the second and third trimesters of pregnancy. The median pretreatment platelet count was 28 × 109/l. The patients received one to seven anti-D infusions at a mean dose of 62·7 µg/kg, and the response rate to anti-D was 75%. A haemoglobin decrease of > 2·0 g/dl occurred only once. Fetal hydrops was not identified by ultrasonography. The direct antiglobulin test was positive in three out of seven Rh+ newborns, none of whom was anaemic or jaundiced. Anti-D is effective and appears to be safe for both mother and fetus.
Eligible women had ITP (George et al, 1996) requiring treatment, a platelet count ≤ 55 × 109/l, were Rh(D) positive and in the second or third trimester of pregnancy. Exclusion criteria were previous splenectomy, ongoing haemorrhage, history of serious reactions to plasma products, haemoglobin < 9·0 g/dl and treatment with anti-D or IVIG within 1 week before entry to the study. Prednisone was allowed if at a stable dose of ≤ 20 mg/d for at least 2 weeks before study entry. Institutional review board-approved informed consent was obtained from all patients.
Anti-D (WinRhoSDF; Cangene, Winnipeg, Canada) was infused at 50–70 µg/kg over 3–15 min. To minimize reactions, paracetamol (650 mg) and prednisone (20 mg) were administered as premedications.
Fetal sonograms were performed at inclusion and repeated monthly until delivery. Complete blood counts (CBC) were initially performed weekly and then twice a month until delivery. Blood type, direct antiglobulin test (DAT), CBC, reticulocyte count and bilirubin level were measured in the neonates.
Partial response (PR) to anti-D was defined as a platelet level > 50 × 109/l and an increase of at least 20 × 109/l within 1 week of treatment; and a complete response (CR) was defined as a platelet count ≥ 150 × 109/l.
Eight women with a median age of 36 years and a median platelet count of 28 × 109/l were included. The median duration of ITP was 5 months, and the median gestational age was 34 weeks (Table I). They each received one to seven infusions of anti-D at a median dose of 4500 µg (62 µg/kg). Six patients (75%) responded (one CR, five PR) by d 7 after the first infusion. The median platelet increase was 54 × 109/l (25–125 × 109/l). During the pregnancy, two patients (nos 3 and 6) received only anti-D; three patients responded to anti-D while continuing 10–20 mg/d prednisone (nos 2, 4 and 8); and three, including the two non-responders (nos 1, 5 and 7), received additional therapy before delivery (Table I).
|Gestational age at |
|Duration of |
|Previous treatment |
|Anti-D infusion (no.), dose (µg)/ time between infusions (d)||Platelet count (× 109/l) |
|Platelet count (× 109/l) on d 7 after each IV anti-D||Other medication |
|Related adverse events |
|1/28||15||24||Pred, IVIG, |
|(1) 3600 |
| 74 |
| – |
MP 1 g, IVIG 1 g/kg
MP 1 g, IVIG 1 g/kg
MP 1 g, IVIG 1 g/kg
|Headache and nausea after |
2nd and 3rd infusions,
dizziness and nausea
after 7th infusion.
*Received IVIG and MP in combination with anti-D
as she was supposed to deliver
a week later and was feared to relapse.
|2/23||38||4||Pred.||(1) 4500||39||103||Ongoing pred. 20 mg/d||None|
|4/36||34||6||Pred.||(1) 5700||17||57||Ongoing pred. 20 mg/d||None|
|5/37||14||1||Pred, IVIG||(1) 6000 |
| 43 |
66 (d 3)
3 (d 4)
| – |
IVIG 1 g/kg
|Chills, fever, headache and |
fatigue 2–5 d after each
infusion, haemolytic anaemia
(Hb decrease of 3·2 g/dl)
|6/37||37||23||IV anti-D||(1) 4500||55*||120||None||Headache, eczema |
*Was scheduled for a caesarean
section 7 d later
|7/31||36||1||None||(1) 6000||10||47 (d 3)||IVIG 1 g/kg after |
d 3 (just before del.)
|8/46||20||4||Pred.||(1) 3900||46*||171||Pred. was tapered from |
20 to 10 mg/d
*Was treated with anti-D
to allow the tapering of pred.
that was not well tolerated
Four patients (50%) complained of mild adverse events after anti-D (Table I). The median haemoglobin decrease was 1·1 g/dl; only patient 5 had a decrease > 2·0 g/dl (3·2 g/dl).
Hydrops fetalis was not detected on ultrasonography. The median gestational age at birth was 38 weeks, the median birthweight was 2·9 kg, and the Apgar scores were ≥ 8 (Table II). Seven babies were Rh(D) positive, and the DAT was positive in three; one case (no. 3) resulted from an ABO incompatibility as demonstrated by elution. Only one (DAT negative) newborn (no. 4) was anaemic (see Table II). The median bilirubin level was 40·2 μmol/l at birth (normal 30·8–50 μmol/l). Only one baby (no. 6) had jaundice, which resolved promptly with phototherapy. His DAT was negative, he was not anaemic, was breastfed, and his older sibling had also had jaundice requiring phototherapy after birth.
|Gestational age |
|Last anti-D infusion |
received by the mother
(d before del.)
(1 min/5 min)
|Lowest platelet |
count (× 109/l)
after birth (d)
|Clinical examination |
within 5 d
|5||36||−5||2·9||9/9||O+||–||23·0||NA||220 (1)||NA||Extra digit/toe on left hand and foot, |
immature reflex system ‡
|6||38||−7||3·3||9/9||O+||–||20·0||3·1||51 (5)||39·3/37·6||Jaundice on d 3§|
The management of ITP during pregnancy may be difficult for several reasons: IVIG and/or prednisone may be ineffective or toxic; it is best to avoid intrapartum splenectomy; and a platelet count ≥ 50 × 109/l is usually required for delivery (Letsky & Greaves, 1996). Therefore, it was logical to test anti-D treatment of ITP during pregnancy. The widespread, antepartum use of anti-D for Rh prophylaxis meant that there was less concern planning this pilot study than there would have been for another medication not previously used in pregnancy.
In this study, six out of eight patients responded after the first treatment, similar to the 72% response rate reported outside pregnancy (Scaradavou et al, 1997). However, four out of six responders received additional therapy to attain a platelet count adequate for delivery or for epidural anaesthesia. Therefore, although anti-D is effective, supplementary treatment with corticosteroids and IVIG may be required, especially at term.
As expected, the toxicity of anti-D in mothers was comparable to that observed outside pregnancy with mild reactions in half the patients and a single case of haemoglobin decrease > 2 g/dl.
Anti-D is a polyclonal antibody predominantly of IgG subclasses I and III that could cross the placenta. In this study, although four out of eight mothers received treatment at least 2 weeks before delivery and two received multiple infusions, no cases of hydrops fetalis or neonatal haemolysis were observed. The high avidity of anti-D for Rh(D)-positive maternal red cells presumably facilitated the prompt removal of ‘free’ anti-D from the maternal circulation, limiting its availability for transplacental passage. Infrequent cases of fetal and/or neonatal haemolysis might have occurred in a larger study.
This study provides evidence for both the efficacy and the safety of anti-D in ITP during the second and third trimesters of pregnancy. However, the number of patients included was relatively low so, pending additional data, we believe that anti-D during pregnancy should be limited to the following situations: (1) as a second-line therapy in patients who do not tolerate or respond to steroids and/or IVIG; and (2) if needed, in combination with IVIG and/or steroids to achieve a safe platelet count at term. In both situations, monitoring of the fetus and newborn is recommended given the risk of haemolysis.
Dr Michel was partially supported by the Laboratoire Français du Fractionnement et des Biotechnologies (LFB), Les Ulis, France.