International Journal of Gynecology and Obstetrics (2006) 95, 115 120

www.elsevier.com/locate/ijgo

CLINICAL ARTICLE

Supportive management of pregnancy-associated aplastic anemia

J.Y. Kwon a, Y. Lee a, J.C. Shin a, J.W. Lee b, J.G. Rha a, S.P. Kim a,*
Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea b Department of Internal Medicine/Division of Hematology, College of Medicine, The Catholic University of Korea, Seoul, Korea
Received 24 April 2006; received in revised form 29 June 2006; accepted 19 July 2006
a

KEYWORDS
Pregnancy-associated aplastic anemia; Supportive management; Transfusion; Prognosis

Abstract Objective: To examine maternal and fetal outcomes of pregnancy-associated aplastic anemia treated with supportive care. Methods: From January 1995 to December 2004, 14 women newly diagnosed as having pregnancy-associated aplastic anemia were recruited for the study. Results: Diagnosis was made during the second or third trimester for 11 (78%) of the 14 patients, and 3 of the 8 severe cases of aplastic anemia were diagnosed at initial presentation. All patients had conservative management with transfusions but no specific immunologic or hormonal therapy during pregnancy. Of the 12 women eligible for follow-up, 1 achieved complete remission and 8 achieved partial remission after delivery. The pregnancies progressed uneventfully in most cases. Conclusions: This study demonstrated favorable maternal and neonatal outcomes with transfusion support alone for pregnancy-associated aplastic anemia. D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
* Corresponding author. Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, #62 Yeouido-dong, Youngdeungpo-ku, 150-010, Seoul, Korea. Tel.: +82 2 3779 1217; fax: +82 2 3779 1930. E-mail address: spkim@catholic.ac.kr (S.P. Kim).

Aplastic anemia is a rare but serious disease characterized by diminished numbers of hematopoietic precursor cells in the bone marrow. Stem cell failure can be either congenital or acquired. Causative factors for acquired aplastic anemia include

0020-7292/$ - see front matter D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2006.07.005

116 exposure to radiation, some viruses, and some drugs or other organic compounds [1,2]. Aplastic anemia has been reported to occur occasionally in pregnancy. Despite its rarity, it is thus important to know how to recognize and treat this condition because it poses risks to both mother and fetus [3,4]. It is unclear whether pregnancy itself causes bone marrow failure. Pregnancy as a possible cause of aplasia has been suggested on the basis that an imbalance between levels of erythropoietin and placental lactogen can lead to suppression of hematopoiesis [5]. This theory has been supported by the clinical observation that the aplasia associated with pregnancy is frequently self-limited, ending with delivery [6]. Yet, although some women who experience aplasia during their first pregnancy experience it again in subsequent pregnancies [7], some investigators have suggested a casual rather than causal relationship between pregnancy and aplastic anemia, sometimes resulting from the worsening of an unidentified pre-existing cytopenia the prognosis of which being unrelated to pregnancy [8,9]. Since it was first described [10], general information on pregnancy-associated aplastic anemia has been available from case reports [3,7,8,11 14]. Evidence to date indicate maternal mortality occurring in up to 50% of cases and fetal complications in up to 60% of cases [3,7,13]. However, data are few and limited to reports sometimes published decades ago. Given the recent advancements in therapeutic strategies and supportive management, there is a need to reconsider the clinical outcomes of pregnancy-associated aplastic anemia. The present study examined the clinical course of pregnancy-associated aplastic anemia at a tertiary medical center over a period of 10 years.

J.Y. Kwon et al.

2. Patients and methods

A total of 32 pregnant women with aplastic anemia visited the pregnancy clinic of the Catholic University of Korea, College of Medicine, Seoul, Korea, from January 1995 to December 2004. Of these, 14 women met the criteria for pregnancy-associated aplastic anemia proposed by Snyder and colleagues [15]: (1) identification of disease after the onset of pregnancy; (2) no evidence of any causes known to induce classic aplastic anemia; (3) decrease in all blood cell counts and blood cell elements (hemoglobin concentration b 10.5 g/dL, white blood cell (WBC) count b 5 109/L, platelet count b100 109/ L); and (4) hypoplastic bone marrow on biopsy. Paroxysmal nocturnal hemoglobinuria was excluded by flow cytometry, and myelodysplastic syndrome or other hematologic malignancies were also excluded by core biopsy and bone marrow aspiration followed by cytogenetics studies. Blood tests were done monthly following diagnosis except in severe cases, in which they were done at weekly intervals. Disease severity was defined and modified based on previous definitions [16,17]. Severe aplasia was defined as 2 or more of the following: an absolute neutrophil count less than 0.5 109/L; a platelet count less than 20 109/L; and a corrected reticulocyte count less than 1%, in association with either a marrow cellularity less than 25% or a marrow cellularity less than 50% but with less than 30% of hematopoietic cells [16]. Moderate aplasia was defined as nonsevere aplasia requiring transfusion either persistently or intermittently, and mild aplasia was defined as nonsevere aplasia not requiring transfusion [17]. Blood transfusions were performed to maintain hemoglobin levels

Table 1
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Clinical and hematological profiles of the 14 patients at presentation

Age (years) 28 34 30 24 38 24 30 32 30 36 28 30 31 28 Gravidity GA (weeks) 38 40 20 37 34 8 36 12 24 38 30 16 8 18 Hb (g/dL) 8.3 9.2 5.5 8.6 9.9 10.2 6.0 9.5 6.8 8.3 10.0 9.0 8.7 7.8 WBC ( 109/L) 4.8 5.0 2.1 2.5 4.9 3.8 3.0 4.7 4.2 4.5 4.8 4.5 3.4 3.7 Neutrophil count ( 109/L) 3.2 2.3 0.5 0.7 3.2 2.3 0.9 1.6 3.1 3.1 2.9 2.7 2.5 0.7 Platelet count ( 109/L) 40 80 37 10 47 60 10 44 28 9 41 53 25 19 Corrected reticulocyte count (%) 2.0 2.5 0.3 1.6 1.2 1.8 1.5 2.2 2.1 1.0 2.0 1.5 1.7 1.0 BM cellularity (%) 30 20 10 10 b10 2030 b10 2030 1020 1020 20 1020 2030 1020

2 1 2 1 9 1 1 1 1 1 1 1 1 1

Abbreviations: BM, bone marrow; GA, gestational age; Hb, hemoglobin; WBC, white blood cell count.

Supportive management of pregnancy-associated aplastic anemia higher than 8 g/dL and platelet counts at least 20 109/L. Some exceptions to this indication were made on a case-by-case basis. Hematologic response was defined according to the following: complete remission entailed a neutrophil count greater than 2.0 109/L and a platelet count greater than 100 109/L; partial remission entailed a neutrophil count greater than 1.0 109/L and a platelet count greater than 30 109/L; and nonresponders remained transfusion-dependent [17]. For patients requiring platelet transfusions frequently, platelets from a single donor were used whenever possible.

117

3.4. Neonatal outcomes

There were no fetal or neonatal deaths but there was 1 spontaneous abortion. The 5-min Apgar score was 8 or higher for all newborns. One infant (of patient 14) developed anemia 20 days after birth and blood tests showed a hemoglobin concentration of 6.7 g/dL. The anemia spontaneously improved after a 60-mL transfusion of packed red blood cells.

3.5. Postpartum maternal outcomes

Aplasia during pregnancy was mild in 4 of the 12 patients eligible for follow-up after delivery, and it was moderate in 1 and severe in 7. Among the 4 patients who had mild aplasia during pregnancy, 3 experienced little change after delivery; patient 1, however, developed severe aplasia 3 months after delivery and had a bone marrow transplantation (BMT) 5 years after delivery. One patient with moderate aplasia achieved a partial remission 1 week after delivery. Of the 7 patients with severe aplasia, 1 (patient 3) had a full recovery 1 year after delivery and has remained in complete remission for the past 7 years; 4 achieved a partial remission within 2 months of delivery but disease relapsed in 1 (patient 10) 24 months after delivery; and the remaining 2 (patients 5 and 7) had antilymphocyte globulin treatment 5 and 8 months postpartum, respectively, but did not respond. One of them underwent BMT 16 months after she was delivered. Overall, 2 patients (patients 1 and 5) who underwent BMT eventually achieved complete remission. Postpartum treatment and outcomes are summarized in Table 2.

3. Results
3.1. Baseline characteristics
The median follow-up period was 61 months (range, 11126 months) and the mean F S.D. gestational age at the time of diagnosis was 26.3 F 12.4 weeks. When the disease was diagnosed, 7 patients (50.0%) were in the third trimester of pregnancy, 4 (28.6%) were in the second trimester, and 3 (21.4%) were in the first trimester. Demographic and hematologic data at diagnosis for all 14 patients are shown in Table 1.

3.2. Prenatal and intrapartum care

In addition to the 3 patients with severe aplastic anemia at diagnosis, 5 patients experienced gradual deterioration as pregnancy progressed and were eventually categorized as having severe aplastic anemia. For all patients the management approach was supportive care in the form of blood transfusions. Transfusions were given to 7 patients (53.8%) during the prenatal period, and to 13 patients (92.8%) during the intrapartum period for a safe delivery. Two patients experienced frequent episodes of epistaxis and 4 had patechiae spread over their bodies, and these were associated with their aplastic anemia. Detailed management is shown in Table 2.

4. Discussion
Since aplastic anemia associated with pregnancy was first reported a century ago [10], many case reports followed [8,1114]. However, although new antibiotic agents and advances in transfusion medicine have lead to improvements in supportive management for this disease, there is a lack of systematic data. This study presents recent experience with improved supportive care in a series of patients whose condition was managed at a single center. Pregnancy-associated aplastic anemia is known to be a life-threatening disorder, with a reported maternal mortality of 20% to 60% [3,7,12]. Despite this dismal prognosis, no maternal death occurred with supportive management in the course of the present study. Four patients requiring further

3.3. Pregnancy outcomes

There were 10 uneventful pregnancies and the remaining 4 were complicated by pre-eclampsia (patient 1), intrauterine growth restriction (patient 4), spontaneous abortion (patient 8), and preterm delivery (patient 11) (Table 2). Of the 14 patients, 10 had a vaginal delivery 4 underwent cesarean section for obstetrical indications.

118

Table 2
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Clinical course and final outcome of the 14 patients

Grade at diagnosis (GA, weeks) Mild (38) Mild (40) Severe (20) Mod (37) Mild (34) Mild (8) Mod (36) Mild (12) Mild (24) Severe (38) Mild (30) Mild (16) Mod (8) Severe (18) Disease progression (GA, weeks) Severe (38) Severe (38) Severe (37) Mod (18) Mod (35) Severe (35) Severe (15) Transfusion (Unit)a PRC /2 / 14/2 /2 /4 / /5 2/ / /2 / /2 4/2 2/3 PC /1 / / 10/5 /18 /5 /10 /6 /10 /24 /5 10/10 10/10 6/ SDP / / 19/3 / /4 / / / 4/ /4 / / / /3 Pregnancy duration (weeks) 38 40 38 39 39 40 38 19 38 38 36 37 38 38 Pregnancy outcome Newborn outcome Postpartum treatment Maternal outcome

PIH IUGR Abortion Preterm delivery

2800 3200 3400 2600 3900

g, g, g, g, g,

good good good good good

3200 g, good 2900 g, good 150 g, death 2900 g, good 3000 g, good 2300 g, good 2800 g, good 2800 g, good 3700 g, anemia

BMT after 5 years Supportive, TI Androgens after 1 week Not assessed ALG, Cs after 8 months, BMT after 16 months Supportive, TI ALG after 5 months Supportive, TI Not assessed Supportive, TI Supportive, TI Supportive, TI Supportive, TI Supportive, TI

NR (up to BMT) PR CR after 1 year Lost to follow-up NR (up to BMT) PR NR PR Lost to follow-up PR, relapse after 2 years PR PR PR PR

ALG, antilymphocyte globulin; BMT, bone marrow transplantation; CR, complete remission; Cs, cyclosporine; GA, gestational age; IUGR, intrauterine growth restriction; NR, nonresponder; PC, platelet concentrate; PIH, pregnancy-induced hypertension; PR, partial remission; PRC, packed red blood cells; PSD, platelet from single donor; TI, transfusion-independent. a Transfusion during prenatal care/transfusion for delivery.

J.Y. Kwon et al.

Supportive management of pregnancy-associated aplastic anemia treatment after delivery responded well to BMT or immunosuppressive therapy. Considering that 8 of the 14 patients were ultimately diagnosed with severe aplasia, the absence of maternal deaths in this study is in striking contrast to the published rates of maternal mortality from this disease [7,18]. Recently, a report from India showed a modestly improved outcome, but the maternal mortality rate still was 20% [3]. Therefore, although these recent results are in favor of supportive management, large studies are needed to determine the best prenatal strategy. Pregnancy outcome has also been reported to be unsatisfactory. A summary of the published reports showed a preterm birth rate of 12.1%; an intrauterine death rate of 16.7%; a stillbirth rate of 15.1%; and a spontaneous abortion rate of 16.7%, while only 39.4% of patients had uncomplicated pregnancies [3]. However, in the present study, 12 (85.7%) of 14 women had full-term pregnancy. Unlike in these reports, pregnancy outcome was not significantly affected in this study. In general, treatment for aplastic anemia includes withdrawal from offending drugs, supportive care, and some form of definitive therapy. Bone marrow transplantation has been reported to be the most effective treatment, with a 5-year survival of 56% to 89% [19]. However, BMT is contraindicated during pregnancy because it requires high-doses of immunosuppressive agents or radiation therapy, which would be toxic to the fetus [7]. Although case reports have suggested a promising result with antilymphocyte immunoglobulin or cyclosporine therapy during pregnancy [3,4,7], there is currently little agreement on the universal use of these therapies. The role of androgens is not clear [20], and androgen treatment may cause the virilization of female fetuses [18]. The efficacy of corticosteroids or granulocyte colony-stimulating factor is also equivocal [4]. Overall, current evidence does not favor the routine use of any drug therapy in the treatment of pregnancy-associated aplastic anemia. Earlier case reports have proposed pregnancy termination as an alternative approach [3,7,21]. Based on their experience of 5 cases, Aitchison and colleagues [7] proposed to consider early termination followed by BMT for women with severe aplastic anemia diagnosed in the first trimester of pregnancy. In the present series, however, all 14 patients received supportive care until delivery, and their pregnancies were uneventful in most cases. Of note, 3 women who were diagnosed as having severe aplastic anemia in the first half of their pregnancies were delivered at term owing to intensive supportive care. Patient 3 completed her

119

pregnancy uneventfully, with transfusions of red cells and platelets at weekly and then biweekly intervals. Although BMT is a definitive therapy for aplastic anemia, the best time for BMT has not yet been clearly defined. Doney and associates [22] have suggested potential drawbacks to delaying BMT after delivery, noting that 2 of 4 patients who underwent delayed BMT recurrently experienced graft rejection. In their study, those events were attributed to an increased sensitization due to the frequent transfusions necessary to delay BMT [22]. In the present study, however, the 2 patients who underwent delayed BMT after delivery achieved complete remission and remain in good health. Further supported by reports that spontaneous recovery may occur after delivery [5,23,24], the results of the present study suggest that women with pregnancy-associated aplastic anemia can look forward to a satisfactory pregnancy outcome when they receive meticulous supportive care at a medical center with access to blood transfusions and hematologic management. To the best of the authors knowledge, this study includes the largest number of patients diagnosed as having the disease and treated at a single center. In addition to offering an overview of recent outcomes of this rare disease, this study will contribute to the accumulation of data towards the best strategy.

References
[1] Issaragrisil S, Kaufman DW, Anderson T, Chansung K, Thamprasit T, Sirijirachai J, et al. Aplastic Anemia Study Group. Low drug attributability of aplastic anemia in Thailand. Blood 1997;89:4034 9. [2] Bacigalupo A, Oneto R, Bruno B, Socie G, Passweg J, Locasciulli A, et al. Working Party on Severe Aplastic Anemia of the European Group for Blood and Marrow Transplantation. Current results of bone marrow transplantation in patients with acquired severe aplastic anemia: report of the European Group for Blood and Marrow transplantation. Acta Haematol 2000;103:19 25. [3] Choudhry VP, Gupta S, Gupta M, Kashyap R, Saxena R. Pregnancy associated aplastic anemia: a series of 10 cases with review of literature. Hematology 2002;7:233 8. [4] Ohba T, Yoshimura T, Araki M, Miyoshi J, Yonemura Y, Matsuura K, et al. Aplastic anemia in pregnancy: treatment with cyclosporine and granulocytecolony stimulating factor. Acta Obstet Gynecol Scand 1999;78:458 61. [5] Fleming AF. Hypoplastic anemia in pregnancy. Clin Haematol 1973;2:477 96. [6] Nissen C. The pathophysiology of aplastic anemia. Semin Hematol 1991;28:313 8. [7] Aitchison RG, Marsh JC, Hows JM, Russell NH, Gordon-Smith EC. Pregnancy associated aplastic anaemia: a report of five cases and review of current management. Br J Haematol 1989;73:541 5.

120
[8] Mandal AK, Nicholas A, Wrigley E, Hopkins RE. Case Report: a case of aplastic anaemia in pregnancy. J Obstet Gynaecol 2005;25:66 7. [9] Oosterkamp HM, Brand A, Kluin-Nelemans JC, Vandenbroucke JP. Pregnancy and severe aplastic anaemia: causal relation or coincidence? Br J Haematol 1998;103:315 6. [10] Ehrlich P. Ueber einen fall von An7mie, mil bemerkungen qber regenative ver7nderungen des knochenmarks [A case of anemia combined with the change of bone marrow finding]. Charite-Ann 1888;13:300 9. [11] Rovinsky JJ. Primary refractory anemia complicating pregnancy and delivery. Obstet Gynecol Surv 1959;14:149 70. [12] Knispel JW, Lynch VA, Viele BD. Aplastic anemia in pregnancy: a case report, review of the literature, and a re-evaluation of management. Obstet Gynecol Surv 1976; 31:523 8. [13] Suda T, Omine M, Tsuchiya J, Maekawa T. Prognostic aspects of aplastic anemia in pregnancy: experience on six cases and review of the literature. Blut 1978;36:285 98. [14] van Besien K, Tricot G, Golichowski A, Padilla L, Hoffman R. Pregnancy-associated aplastic anemia: report of 3 cases. Eur J Haematol 1991;47:253 6. [15] Snyder TE, Lee LP, Lynch S. Pregnancy-associated hypoplastic anemia: a review. Obstet Gynecol Surv 1991;46:264 9. [16] Brodsky RA, Jones RJ. Aplastic anaemia. Lancet 2005;365: 1647 56. [17] Marsh J, Schrezenmeier H, Marin P, Ilhan O, Ljungman P, McCann S, et al. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the

J.Y. Kwon et al.

European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood 1999;93:2191 5. Deka D, Malhotra N, Sinha A, Banerjee N, Kashyap R, Roy KK. Pregnancy associated aplastic anemia: maternal and fetal outcome. J Obstet Gynaecol Res 2003;29:67 72. Tichelli A, Socie G, Henry-Amar M, Marsh J, Passweg J, Schrezenmeier H, et al. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. Ann Intern Med 1999;130: 193 201. Doney K, Pepe M, Storb R, Bryant E, Anasetti C, Appelbaum FR, et al. Immunosuppressive therapy of aplastic anemia: results of a prospective, randomized trial of antithymocyte globulin (ATG), methylprednisolone, and oxymetholone to ATG, very high-dose methylprednisolone, and oxymetholone. Blood 1992;79:2566 71. Deka D, Banerjee N, Roy KK, Choudhary VP, Kashyap R, Takkar D. Aplastic anaemia during pregnancy: variable clinical course and outcome. Eur J Obstet Gynecol Reprod Biol 2001;94:152 4. Doney K, Storb R, Buckner CD, Sanders J, Witherspoon R, Thomas ED. Marrow transplantation for treatment of pregnancy-associated aplastic anemia. Exp Hematol 1985;13:1080 3. Majer RV, Green PJ. Recurrent reversible pure red cell aplasia in pregnancy. Clin Lab Haematol 1988;10:101 3. Baker RI, Manoharan A, de Luca E, Begley CG. Pure red cell aplasia of pregnancy: a distinct clinical entity. Br J Haematol 1993;85:619 22.

[18]

[19]

[20]

[21]

[22]

[23] [24]