Successful management and perinatal outcome of pregnancy complicated with myelodysplastic syndrome

Leukemia Research 26 (2002) 255– 260 www.elsevier.com/locate/leukres

Successful management and perinatal outcome of pregnancy complicated with myelodysplastic syndrome Yuichiro Ikeda a,*, Hideaki Masuzaki a, Daisuke Nakayama a, Takahiro Maeda b, Khaleque Newaz Khan a, Yuko Okita a, Emiko Doi a, Masao Tomonaga b, Tadayuki Ishimaru a b

a Departments of Obstetrics and Gynecology, Nagasaki Uni6ersity School of Medicine, 1 -7 -1 Sakamoto, Nagasaki 852 -8501, Japan Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki Uni6ersity School of Medicine, 1 -7 -1 Sakamoto, Nagasaki 852 -8501, Japan

Received 13 April 2001; accepted 6 July 2001

Abstract Pregnancy complicated with myelodysplastic syndrome (MDS) is rare and case management is controversial. We report six cases of MDS that were successfully managed during pregnancy including uneventful transvaginal delivery and satisfactory postpartum clinical prognosis. Two patients with MDS who became pregnant twice had normal uneventful deliveries showing no deterioration of MDS. Our findings suggest that pregnancy should be allowed to full-term in MDS patients, especially those of the refractory anemia type, but strict management should be provided before, during and after pregnancy. Pancytopenia might develop during pregnancy but the likelihood of transformation of MDS to leukemia due to pregnancy is remote. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Myelodysplastic syndrome; Refractory anemia; Pregnancy; Vaginal delivery; Management; Outcome

1. Introduction Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders characterized by ineffective hematopoiesis with myelodysplasia and are associated with a high risk of progression to acute leukemia. In 1982, the French –American – British (FAB) classification was introduced, which divided MDS into five categories according to bone marrow and peripheral blood smear findings [1]. These categories include: (1) refractory anemia (RA); (2) RA with ring sideroblasts; (3) RA with excess of blasts (RAEB); (4) chronic

Abbre6iations: MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, RA with excess of blasts; CMML, chronic myelomonocytic leukemia; RAEB-t, RAEB ‘in transformation’; FAB, French– American–British classification; VD, vaginal delivery. * Corresponding author. Tel.: + 81-95-849-7363; fax: + 81-95-8497365. E-mail address: [email protected] (Y. Ikeda).

myelomonocytic leukemia (CMML); and (5) RAEB ‘in transformation’(RAEB-t). Although the majority of patients with MDS are elderly, an increasing number of younger patients are being reported in recent years. The effect of MDS on the outcome of pregnancy is controversial. For example, Siddiqui et al. [2] reported that prognosis of pregnancy complicated with MDS is very poor. However, several other investigators have indicated that prognosis is not always poor [3–7]. In this regard, the exact influences of MDS on obstetrical management and maternal prognosis during the postpartum period complicated with MDS are not clear at present. The purpose of this report was to examine the influence of MDS on obstetrical management and maternal prognosis during the postpartum period. For this purpose, we compared our cases (four patients, six deliveries; two patients had two deliveries) of MDS, type RA, to those previously reported in the literature.

0145-2126/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 1 ) 0 0 1 2 5 - 4

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2. Case report Tables 1– 3 summarize the clinical findings in our six cases and those reported earlier. All cases were diagnosed as MDS-RA before pregnancy, based on the results of bone marrow aspiration. In addition, bone marrow chromosomal analysis was performed in three patients and was found abnormal in two. None of the patients developed leukemia after delivery and no chemotherapy and/or bone marrow transplantation were given (Table 1). Although all of our patients had the diagnosis of MDS made `5 years before the pregnancy, one patient had the disease for 13 years before she became pregnant. These cases represent a very small fraction of patients with this disease. All patients had uneventful transvaginal delivery performed by induction of labor at full term. Concentrated red blood cells were transfused in two cases for the correction of severe anemia while concentrated platelets were transfused in four cases due to low platelets count and to prevent massive bleeding. One patient lost 885 g of blood during early puerperal period because of uterine atonic bleeding. One patient developed pre-eclampsia during pregnancy and two cases with low birth weight infants (Table 2). During the antepartum period, gradual exacerbation of anemia was observed in three cases and platelets count decreased in all six cases. However, white blood cell count did not change in all cases. In contrast, during the postpartum period, the anemia was stabilized relatively and was improved in four cases. The platelets count was increased in four cases. Thus, the prognosis of MDS remains stable in all cases. All of them were asymptomatic at the last follow-up (Table 3).

3. Discussion This is the first report describing the successful management of six pregnant women with MDS at a single institution. MDS was established as a disease category in 1982 by FAB and categorized into five types according to bone marrow and peripheral blood findings [1]. The majority of patients with primary MDS are usually over 50 years of age and the number of reported young adult cases in childbearing age is small. Previous studies have reported a few pregnancy cases complicated with MDS. To date, there is no standardized protocol for the management of pregnancy cases complicated with MDS and maternal prognosis is not well clarified, probably because of the small number of young adult cases in the childbearing age. The most frequent finding in pregnant women with MDS is severe anemia of unknown origin, followed by bleeding tendency due to low platelet count. Almost all

cases reviewed in the lecture were diagnosed as MDS during the first or second trimester except for four cases; three were diagnosed before pregnancy [4,10,11] while the other was diagnosed at postpartum [2]. All our four patients were diagnosed before pregnancy; in three patients, purpura was a presenting symptom with the remaining patient being diagnosed as having anemia on collective medical examination. Other symptoms included general fatigue and fever (Table 1). Thus, MDS should be considered in the differential diagnosis of severe anemia and thrombocytopenia of unknown origin in pregnant women. In general, hemoglobin concentration is low in early and mid-pregnancy, and near term. The average hemoglobin concentration in healthy women with normal iron stores is ] 11 g/dl. Our patients had low hemoglobin concentrations at early pregnancy and four cases required concentrated red blood cells transfusion. It was not clear whether the anemia was due to iron deficiency anemia or worsening of MDS. Because MDS is an irreversible disease, worsening of MDS in our cases should result in failure of improvement of anemia at postpartum. Severe anemia, especially in mid-pregnancy, may influence fetal growth and result in intrauterine fetal death or intrauterine growth retardation. Therefore, severe anemia detected in midtrimester must be corrected promptly. Refractory anemia was the type of MDS in our four patients. Bone marrow examination and peripheral blood analysis were performed in all patients. In one case, bone marrow examination was performed after delivery and showed no significant changes. The other patients were followed-up by regular peripheral blood examinations, which did not show a sign of transformation to acute leukemia, and none required chemotherapy or bone marrow transplantation. Based on the previous reports summarized in Table 1, RA was reported in ten cases, RAEB in three cases, RAEB-t in three cases and the unknown type in two cases. One Japanese case was reported to have transformed to acute leukemia [8], although other patients showed stable prognosis [3,5,6,10,11]. However, in other reports, maternal prognosis was poor, especially MDS in the five cases reported by Siddiqui et al. [2]. All died due to worsening of their condition. Among the 23 patients reported so far, 3 of 14 RA patients, including 4 patients of our series, died due to transformation to acute leukemia. On the other hand, transformation to acute leukemia was reported in 2 of the 3 RAEB patients and 1 of 1 RAEB-t patient. Generally, the prognosis of MDS-RA is better than that of RAEB and RAEB-t, similarly these data suggest that the prognosis of MDS-RA patients at postpartum is apparently better than that of RAEB and RAEB-t patients, who are at a high risk of transformation to acute leukemia.

Y. Ikeda et al. / Leukemia Research 26 (2002) 255–260

257

Table 1 Profiles of pregnant women with MDS Reference

Case no.

Age

Gravidity

Parity

[3]

1

20

1

0

[6]

2

30

1

0

[10]

3

25

1

1

[8]

4a

32

0

0

4b 5

33 38

1 0

1 0

[11]

6

32

0

0

[5]

7

31

0

0

8

27

0

0

9

31

1

–

10

31

3

–

11

32

1

–

12

31

0

–

13

22

1

–

14

28

1

1

15

30

–

–

16

28

–

–

17

32

2

2

[4]

18

47

10

10

[7]

19

34

–

–

Present study

20

21

0

0

21

28

0

0

22a

18

0

0

22b 23a

27 26

4 1

1 0

23b

27

2

1

[2]

[9]

Time of onset

Time of diagnosis

FAB

After delivery outcome

During pregnancy at 33 weeks Ten years before pregnancy Four years before pregnancy During pregnancy

Same as onset

RA

Improved

During pregnancy at 22 weeks Two years before pregnancy Same as onset

RA

Improved

Unknown

Improved

RA

No change

RA RAEB-t

Improved Leukemic change (AML)

Several month before Same as onset

RA

No change

RA

Improved

Same as onset

Unknown

Improved

Same as onset

RA

During pregnancy at 30 weeks Same as onset

RAEB

Died after one year (AML) Died after one year (AML) Died after nine months (AML)

Same as onset

RA

Died one month after BMT

Same as onset

RAEB

Died after two years (AML)

Same as onset

RA

Died after about two years (AML)

Same as onset

RAEB

Improved by BMT

Same as onset

RA RAEB

Improved by BMT

Same as onset

RA

No change

Four months before pregnancy Same as onset

RAEB-t

No change

RAEB-t

Improved

Four years before pregnancy One year before pregnancy One year before pregnancy

RA

No change

RA

No change

RA

No change

RA RA

No change No change

RA

No change

During pregnancy at 16 weeks Ten years before pregnancy During pregnancy at 26 weeks Four years before pregnancy Three years after pregnancy 16 yrs old? During pregnancy at 20 weeks During pregnancy at 12 weeks During pregnancy at 16 weeks During pregnancy at 18 weeks During pregnancy at 19 weeks During early pregnancy During pregnancy at 13 weeks Seven months before pregnancy During pregnancy at 38 weeks Six years before pregnancy Six years before pregnancy Five years before pregnancy 13 years before pregnancy

Same as onset

Eight years before pregnancy

RA

RA, refractory anemia; RAEB, RA with excess blasts; AML, acute myelogenous leukemia; BMT, bone marrow transplantation.

258

Table 2 Pregnancy outcome in patients with MDS Treatment

Change of MDS during pregnancy

Outcome/delivery method

1 2 3 4a 4b 5 6 7 8 9

CRC, CP CRC, CP CRC, CP Observation CRC, CP Chemotherapy, CRC, CP PLS, CRC, CP CRC, CP CP Chemotherapy at postpartum Chemotherapy at postpartum Chemotherapy at postpartum Allogeneic BMT Chemotherapy at postpartum Chemotherapy at postpartum Allogeneic BMT Allogeneic BMT CRC, CP CRC CRC, CP, chemotherapy Observation CRC, CP Observation CP CP PSL, CRC, CP

Deteriorated Deteriorated No change No change Deteriorated Deteriorated Deteriorated No change No change Unknown

Elective C/S at 36 weeks VD after induction at 36 weeks Elective C/S at 38 weeks IUFD at 21 weeks Fetal distress/ C/S at 38 weeks Therapeutic abortion at 18 weeks VD after induction at 37 weeks Fetal distress/ C/S at 28 weeks IUFD at 24 weeks IUGR

Unknown

VD at 36 weeks

Unknown

VD at term

Deteriorated Deteriorated

Therapeutic abortion Termination by hysterectomy

Deteriorated

VD at term

NA

Deteriorated Unknown No change No change No change No change Deteriorated No change Deteriorated Deteriorated Deteriorated

Elective C/S at term Therapeutic abortion at 10 weeks VD at term VD at 38 weeks VD at term VD after induction at 38 weeks VD after induction at 37 weeks VD after induction at 39 weeks VD after induction at 38 weeks VD after induction at 38 weeks VD after induction at 38 weeks

Healthy

10 11 12 13 14 15 16 17 18 19 20 21 22a 22b 23a 23b

CRC, concentrated red cells; CP, concentrated platelets; PSL, prednisolone. a Case no. same as Table 1.

Blood loss (g)

600 1520 1400 250 160

Birth weight (g) Survived 3316 2550 50 2840 150 2610 1552

Apgar1/5 min

Complication

10 8/9 8 9/10 6/10

PAIg 167 ng/ml Pre-eclampsia IUGR

2550

8/9

Down syndrome

Endometritis

480 50 295 885 160 425

NA

Healthy 2970

9/10

3170 2090 3020 3300 2310 2810

9/9 9/9 9/10 9/9 9/9 9/9

IUGR, pre-eclampsia PAIg 128.1 ng/ml IUGR, Behcet disease

Y. Ikeda et al. / Leukemia Research 26 (2002) 255–260

Case no. a

Y. Ikeda et al. / Leukemia Research 26 (2002) 255–260

259

Table 3 Peripheral blood (PB) and bone marrow (BM) findings during pregnancy Case no. 20

21

22a

At enrolment WBC (/mm3) RBC (×104/mm3) Hb (g/dl) MCV (m3) PLT (×104/mm3) Erythroblast at PB (%) Myeloblast at BM (%) Chromosome at BM

4900 397 12.2 93.2 11.3 0 0.2 46,XX

3800 389 13.6 114.1 7.2 0 1.2 47,XX,+9/46,XX

4050 256 7.8

2850 332 11.1

5.5 0 0.8 ND

8.8 0 1.2 47,XX,+8/46,XX

At antepartum WBC (/mm3) RBC (×104/mm3) Hb (g/dl) MCV (m3) PLT (×104/mm3) Erythroblast at PB (%)

5700 301 8.4 88.4 4.9 0

3400 242 9.2 111.2 2.9 0

5000 282 9.6

At Postpartum (1 month) WBC (/mm3) RBC (×104/mm3) Hb (g/dl) MCV (m3) PLT (×104/mm3) Erythroblast at PB (%)

3700 361 11.4 96.7 9.6 0

3100 243 8.8 107.4 5.9 0

As shown in Table 3, red blood cell and platelet counts decreased during pregnancy in our cases but white blood cells remained within the normal range. Two cases required blood transfusions because of severe anemia. Previous reports of Japanese patients indicated that almost all cases required blood transfusions. Therefore, it seems that in pregnancy complicated with MDS, blood transfusions are essentially performed for the treatment for anemia. Further, anemia must be treated promptly by the time of the third trimester to prevent possible intrauterine growth retardation and/or intrauterine fetal death. The fall in platelet count during delivery should also be treated immediately with concentrated platelet transfusion to prevent massive blood loss. The method of delivery in patients with MDS is controversial [10]. We selected transvaginal delivery in our cases because the volume of blood loss seemed to be much smaller in this method than by caesarian section. We believe that unless there is maternal or fetal contraindication, vaginal birth is appropriate for delivery. MDS complicated with pregnancy is a rare clinical condition and its management is controversial at the moment. Based on the results obtained in the present six deliveries and those reported previously, it seems that MDS-RA does not necessarily worsen the course

22b

23a

23b

7.0 0

4600 237 8.9 116.5 5.0 0

4900 281 10.0 111.4 4.4 0

4700 229 7.8 107.0 7.8 0

4000 288 8.3 96.2 6.4 0

3700 282 9.1 101.6 5.6 0

4000 309 10.5 106.5 5.4 0

9400 307 10.3 99.7 4.5 0

of pregnancy and therefore the latter should be allowed to continue to full term. However, strict management of peripheral blood abnormalities and symptoms is necessary during pregnancy and postpartum period. Acknowledgements Y. Ikeda provided the concept, design, analysis of data, contributed patients and drafted the manuscript. H. Masuraki contributed to the study design, provided critical input to the revision, and provided patients for the case histories. D. Nakayama contributed patients and contributed to the concept of the paper. T. Maeda assembled the data. K.N. Khan contributed to the revision. Y. Okita helped to collect the clinical and laboratory data and provided patients for the study. E. Doi helped to collect the clinical and laboratory data and provided patients for the study. M. Tomonaga contributed to the revision of the paper. T. Ishimaru contributed to the revision and gave final approval. References [1] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189.

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