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TPO for ITP in pregnancy

James B. Bussel and Eun-Ju Lee

In this issue of Blood, Kong et al describe a novel approach to immune thrombocytopenia (ITP) in pregnancy.1

In 1990, 3 studies summarized in Bussel et al2 all showed a low incidence of severe fetal thrombocytopenia (10% to 15%) and a very low incidence of intracranial hemorrhage (0.5% to 1%) in infants of mothers with ITP. These findings, combined with the difficulty with fetal blood3 and scalp sampling,4 altered the consensus recommendations on vaginal delivery instead of cesarean section for routine deliveries. The challenge remained of preventing maternal bleeding and allowing epidural anesthesia. Because platelet counts typically fall during the third trimester, the 80 000 to 100 000 × 109/L count required for an epidural, more than enough for safe delivery, often is a difficult platelet threshold to achieve.

Generally accepted treatments of ITP in pregnancy are IV immunoglobulin (IVIG) and steroids. IVIG has a substantial but all-too-temporary platelet effect. It is primarily useful for scheduled, elective delivery or in an emergency if steroids are ineffective. Steroids (prednisone) have little fetal toxicity because of placental 21β hydroxylase. In view of the low required platelet counts during pregnancy (only 20 000 × 109/L), starting with 10 to 20 mg daily of prednisone is often a good approach; higher doses are often needed later in gestation and may not be sufficient.5 A recent study suggested that these 2 main treatments are less effective for ITP in pregnant than in nonpregnant women.6

Second-line treatments are rarely invoked. Rituximab has been accidentally used (not knowing the mother was pregnant), when other treatments had failed, and when the mother herself requires treatment. Fetal toxicity seems low, although clinical and laboratory follow-up has not been comprehensive. Anti-D immunoglobulin is used at 28 weeks (and at delivery) in thousands of rhesus factor–negative pregnancies per year; however, the ITP dose is 10 times as high as for prophylaxis and could result in maternal or fetal hemolysis. Treatment with azathioprine during pregnancy to prevent rejection of a transplanted kidney seems safe for the fetus; however, azathioprin is not very effective in maternal ITP, and onset of its effect requires weeks.

The study by Kong et al treated 31 pregnant women with ITP, almost all during their first pregnancy. The women were selected because they had failed to respond to corticosteroids and/or IVIG. Twenty-three responded, with 10 women achieving a platelet count >100 000 × 109/L and another 13 peaking in the 30 000 to 100 000 × 109/L range. Patients received 300 U/kg of recombinant human thrombopoietin (TPO) for 14 days and were then dosed according to their response. Recombinant human TPO is licensed in China for ITP.

Having another effective, safe agent to use would be useful in pregnant women with ITP. The 2 thrombopoietic agents available worldwide, eltrombopag7 and romiplostim,8 would both be expected to cross the placenta and have been avoided during pregnancy due to concerns of the effects on fetal bone marrow. An unanswered question is whether the thrombopoietic agent described in this study would cross the placenta or appear in breast milk. The authors suggest that the modification of the TPO-like molecule makes this unlikely. The neonatal safety and median 53-week follow-up for growth and development is encouraging, as is the not-increased TPO level in cord blood. There are too few patients to use the low rate of neonatal thrombocytopenia to suggest that the TPO agent affected the fetal count. Although small case reports suggest maternal efficacy of TPO agonists in very refractory ITP cases in pregnancy,9 rigorous studies are needed of romiplostim and eltrombopag to see if the findings of Kong et al can be replicated with the 2 more widely available agents. This treatment could greatly facilitate management of ITP in pregnant women if it is confirmed to be both safe and effective.

Footnotes

  • Conflict-of-interest disclosure: J.B.B. has received clinical research support from Amgen, Boehringer Ingelheim, Novartis, Prophylix Pharma, Protalex, and Rigel and has served as an advisor or consultant for Amgen, Rigel, Grifols, Momenta, Novartis, and UpToDate, Inc. E.-J.L. declares no competing financial interests.

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