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DOI: 10.1055/s-0043-1775837
Primary Immune Thrombocytopenia in Pregnancy: Pathology, Diagnosis, and Management
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by an isolated decrease in the peripheral blood platelet count without a clear cause.[1] The reported annual incidence rate of adult ITP is 2 to 10/100,000 and is higher in women of childbearing age.[2] [3] Many factors increase the difficulty of ITP diagnosis and treatment during pregnancy, such as the decreased platelet count during normal pregnancy, accelerated platelet clearance, surgical delivery, the suspension of treatment, and immunoglobulin G antiplatelet antibodies transferred to the fetus through the placenta.[4] Early identification and correct treatment are crucial to ensuring the safety of mothers and babies.
Studies have shown that serum thrombopoietin (TPO) levels in pregnant women with ITP are higher than those in nonpregnant women with ITP, suggesting that platelet production may be impaired.[5] [6] Elevated estrogen levels during pregnancy can also induce megakaryocyte maturation disorder and apoptosis.[5] [7] In addition, whether the platelet membrane surface glycoprotein IIIa expressed on syncytiotrophoblasts is a potential target of autoantibodies or an inflammatory factor remains to be explored.
In the New England Journal of Medicine, Bussel et al reviewed the management of ITP during pregnancy.[8] Physiological thrombocytopenia is more common in pregnant women, usually starting in the first trimester and gradually decreasing during pregnancy until delivery.[9] This is associated with hemodilution and increased plasma volume.[10] ITP is the most common cause of platelet counts below 80 × 103 per cubic millimeter and of thrombocytopenia in the first and second trimesters in healthy pregnant women. ITP manifests as isolated thrombocytopenia, and these patients have normal peripheral blood smears and show no evidence of having other hematological diagnoses, including hereditary thrombocytopenia, and those caused by drugs, infection, and other causes. A significant response to ITP therapy is also strong diagnostic evidence.[11] The diagnosis of ITP during pregnancy needs to be differentiated from other types of thrombocytopenia, especially gestational thrombocytopenia (GT). GT, by far the most common cause of thrombocytopenia during pregnancy, is associated with hemodilution from increased blood volume and increased platelet destruction as blood flows across the rough placental trophoblast surface.[9] The level of serum TPO in the peripheral blood of pregnant women with ITP is increased, which can be used as a reference index for differentiation from GT.
Although the platelet count decreases in almost all women with ITP during pregnancy, it is not common for women with platelet counts below 30 × 103 per cubic millimeter, and the incidence of bleeding is only slightly higher than that of nonpregnant ITP patients (hazard ratio = 1.83, 95% confidence interval: 0.91–3.65). Compared with nonpregnant women with ITP, women with ITP during pregnancy are more likely to experience worsening thrombocytopenia and treatment adjustment.[12] Platelet counts usually return to prenatal levels after delivery. Most studies have found that ITP does not cause an increase in the risk of common complications of pregnancy, such as preeclampsia, preterm delivery, placental abruption, and thromboembolism.
Regarding management, this review suggested routine follow-up every 4 weeks in the first and second trimesters, then every 2 weeks thereafter, and finally weekly until delivery. The indications for treatment in the first and second trimesters of pregnancy are the same as those in nonpregnant patients with ITP (such as a platelet count < 20 × 103 to 30 × 103 per cubic millimeter, bleeding, or invasive operation). The mode of delivery should be chosen according to obstetrical indications. Platelet counts ≥ 30 × 103 per cubic millimeter in women with vaginal delivery, ≥ 50 × 103 per cubic millimeter in women undergoing caesarean section, and ≥ 70 to 80 × 103 per cubic millimeter in women with intraspinal anesthesia are recommended.
Regulatory agencies have not approved drugs for the treatment of ITP during pregnancy. Prednisone can be considered for first-line treatment, since it becomes inactivated when passing the placental barrier. The initial dose is usually 10 to 20 mg/d and is gradually adjusted to the minimum dose. When glucocorticoid therapy is not effective or when patients are ready to give birth, increasing intravenous immunoglobulin (IVIG) should be considered. The common dose is 400 mg/kg/d × 5 days or 1 g/kg/d × 1 ∼ 2 days.
Experts have not yet reached a consensus regarding the second-line treatment for pregnancy complicated with ITP. Rituximab may affect the immune function of newborns, so it is not recommended for the treatment of ITP during pregnancy. The safety data of immunosuppressants such as azathioprine, dapsone, and cyclosporine are mostly from other disease reports, and there is a lack of sufficient evidence-based medical evidence for pregnant ITP patients. TPO receptor agonists (TPO-RAs) are the first choice for the second-line treatment of ITP and has not been approved by regulators for use during pregnancy. A multicenter prospective study included 31 pregnant women with ITP for whom glucocorticoid and/or IVIG therapy was ineffective. They were treated with recombinant human TPO 300 U/kg/d × 14 days in the second and third trimesters of pregnancy, with an overall effective rate of 74.2% and no obvious adverse reactions.[13] Another retrospective study showed that 77% of pregnant patients with refractory ITP responded to treatment with eltrombopag or romiplostim.[14] As a means of increasing the platelet count before delivery, multiple case reports support the safe and effective administration of TPO-RAs in the third trimester of pregnancy.[15] [16] [17] [18]
In summary, this review provides guidance for managing ITP in pregnant women. The selection of conventional ITP treatment drugs during pregnancy should be based on a pregnant woman's individual situation, pregnancy time, and mode of delivery.
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Conflict of Interest
None declared.
Authors' Contributions
J. L. wrote the paper, L. Z. read and approved the final manuscript.
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References
- 1 Liu XG, Hou Y, Hou M. How we treat primary immune thrombocytopenia in adults. J Hematol Oncol 2023; 16 (01) 4
- 2 Moulis G, Palmaro A, Montastruc JL, Godeau B, Lapeyre-Mestre M, Sailler L. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 2014; 124 (22) 3308-3315
- 3 Lee JY, Lee JH, Lee H. et al. Epidemiology and management of primary immune thrombocytopenia: a nationwide population-based study in Korea. Thromb Res 2017; 155: 86-91
- 4 Obstetrics Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. Expert consensus on diagnosis and treatment of primary immune thrombocytopenia in pregnancy [in Chinese]. Zhonghua Fu Chan Ke Za Zhi 2023; 58 (03) 170-177
- 5 Zhang X, Zhao Y, Li X. et al. Thrombopoietin: a potential diagnostic indicator of immune thrombocytopenia in pregnancy. Oncotarget 2016; 7 (07) 7489-7496
- 6 Frölich MA, Datta S, Corn SB. Thrombopoietin in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998; 179 (01) 100-104
- 7 Dupuis M, Severin S, Noirrit-Esclassan E, Arnal JF, Payrastre B, Valéra MC. Effects of estrogens on platelets and megakaryocytes. Int J Mol Sci 2019; 20 (12) 3111
- 8 Bussel JB, Hou M, Cines DB. Management of primary immune thrombocytopenia in pregnancy. N Engl J Med 2023; 389 (06) 540-548
- 9 Reese JA, Peck JD, Deschamps DR. et al. Platelet counts during pregnancy. N Engl J Med 2018; 379 (01) 32-43
- 10 Provan D, Arnold DM, Bussel JB. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3 (22) 3780-3817
- 11 Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood 2017; 130 (21) 2271-2277
- 12 Guillet S, Loustau V, Boutin E. et al. Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study. Blood 2023; 141 (01) 11-21
- 13 Lee LO, Bateman BT, Kheterpal S. et al; Multicenter Perioperative Outcomes Group Investigators. Risk of epidural hematoma after neuraxial techniques in thrombocytopenic parturients: a report from the multicenter perioperative outcomes group. Anesthesiology 2017; 126 (06) 1053-1063
- 14 Michel M, Ruggeri M, Gonzalez-Lopez TJ. et al. Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study. Blood 2020; 136 (26) 3056-3061
- 15 Bussel JB, Cooper N, Lawrence T. et al. Romiplostim use in pregnant women with immune thrombocytopenia. Am J Hematol 2023; 98 (01) 31-40
- 16 Agarwal N, Mangla A. Thrombopoietin receptor agonist for treatment of immune thrombocytopenia in pregnancy: a narrative review. Ther Adv Hematol 2021; 12: 20 406207211001139
- 17 Howaidi J, AlRajhi AM, Howaidi A, AlNajjar FH, Tailor IK. Use of thrombopoietin receptor agonists in pregnancy: a review of the literature. Hematol Oncol Stem Cell Ther 2022; 15 (01) 1-6
- 18 Purushothaman J, Puthumana KJ, Kumar A, Innah SJ, Gilvaz S. A case of refractory immune thrombocytopenia in pregnancy managed with elthrombopag. Asian J Transfus Sci 2016; 10 (02) 155-158
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Publikationsverlauf
Artikel online veröffentlicht:
18. Oktober 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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References
- 1 Liu XG, Hou Y, Hou M. How we treat primary immune thrombocytopenia in adults. J Hematol Oncol 2023; 16 (01) 4
- 2 Moulis G, Palmaro A, Montastruc JL, Godeau B, Lapeyre-Mestre M, Sailler L. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 2014; 124 (22) 3308-3315
- 3 Lee JY, Lee JH, Lee H. et al. Epidemiology and management of primary immune thrombocytopenia: a nationwide population-based study in Korea. Thromb Res 2017; 155: 86-91
- 4 Obstetrics Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. Expert consensus on diagnosis and treatment of primary immune thrombocytopenia in pregnancy [in Chinese]. Zhonghua Fu Chan Ke Za Zhi 2023; 58 (03) 170-177
- 5 Zhang X, Zhao Y, Li X. et al. Thrombopoietin: a potential diagnostic indicator of immune thrombocytopenia in pregnancy. Oncotarget 2016; 7 (07) 7489-7496
- 6 Frölich MA, Datta S, Corn SB. Thrombopoietin in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998; 179 (01) 100-104
- 7 Dupuis M, Severin S, Noirrit-Esclassan E, Arnal JF, Payrastre B, Valéra MC. Effects of estrogens on platelets and megakaryocytes. Int J Mol Sci 2019; 20 (12) 3111
- 8 Bussel JB, Hou M, Cines DB. Management of primary immune thrombocytopenia in pregnancy. N Engl J Med 2023; 389 (06) 540-548
- 9 Reese JA, Peck JD, Deschamps DR. et al. Platelet counts during pregnancy. N Engl J Med 2018; 379 (01) 32-43
- 10 Provan D, Arnold DM, Bussel JB. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3 (22) 3780-3817
- 11 Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood 2017; 130 (21) 2271-2277
- 12 Guillet S, Loustau V, Boutin E. et al. Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study. Blood 2023; 141 (01) 11-21
- 13 Lee LO, Bateman BT, Kheterpal S. et al; Multicenter Perioperative Outcomes Group Investigators. Risk of epidural hematoma after neuraxial techniques in thrombocytopenic parturients: a report from the multicenter perioperative outcomes group. Anesthesiology 2017; 126 (06) 1053-1063
- 14 Michel M, Ruggeri M, Gonzalez-Lopez TJ. et al. Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study. Blood 2020; 136 (26) 3056-3061
- 15 Bussel JB, Cooper N, Lawrence T. et al. Romiplostim use in pregnant women with immune thrombocytopenia. Am J Hematol 2023; 98 (01) 31-40
- 16 Agarwal N, Mangla A. Thrombopoietin receptor agonist for treatment of immune thrombocytopenia in pregnancy: a narrative review. Ther Adv Hematol 2021; 12: 20 406207211001139
- 17 Howaidi J, AlRajhi AM, Howaidi A, AlNajjar FH, Tailor IK. Use of thrombopoietin receptor agonists in pregnancy: a review of the literature. Hematol Oncol Stem Cell Ther 2022; 15 (01) 1-6
- 18 Purushothaman J, Puthumana KJ, Kumar A, Innah SJ, Gilvaz S. A case of refractory immune thrombocytopenia in pregnancy managed with elthrombopag. Asian J Transfus Sci 2016; 10 (02) 155-158