Ritodrine-induced agranulocytosis

Int J Gynecol

International

Obstet,

of Gynecology

Ritodrine-induced M. Muroa, “Department National

Nagasaki

and Obstetrics

agranulocytosis M. Oga”, Y. Ito”, M. Hiraib and H. Sugimori”

H. Shonoa,

of Obstetrics

Hospital,

329

1991, 36: 329-331

Federation

and Gynecology. und “Deportment

Saga Medical of Ohstctrics

School.

Saga,

hDc~partnwnt

und G.wwolog~.

of Obstetrics

T.vu.shimrr Irulrortr

and G~wcolog~~.

Ikcpittrl.

Nagasaki

Nagtrsakiqwc~ (Japan)

(Received February I I th. 199 I ) (Revised and accepted April 4th. 1991)

Abstract This is the first reported case of development of agranulocytosis induced by continuous intravenous infusion of a large quantity of ritodrine hydrochloride for tocolysis. It is suspected that the pathophysiological mechanism is a doserelated toxic reaction and a cell loss maturation process of myelocytes.

Keywords: Agranulocytosis;

chloride; Threatened

Ritodrine hydropremature labor.

Introduction Ritodrine hydrochloride (ritodrine), a &-adrenergic agonist, has been widely used in the treatment of threatened premature labor, although its use has been associated with such side effects as pulmonary edema, myocardial ischemia, and neutropenia [l-3]. This is the first reported case of agranulocytosis induced by continuous intravenous infusion of a large quantity of ritodrine for tocolysis [4]. Case report A 24-year-old woman who was 25 weeks pregnant with twins, gravida 0, para 0, blood type A, anti-D(-), and anti-E(-), was admitted to Tsushima Izuhara Hospital for 0020-7292/91/$03.50 0

1991 International

Published

and Printed

Federation in Ireland

of Gynecology

and Obstetrics

tocolysis. She had no history of leukopenia or recent exposure to any drugs or toxins. White blood cell count was 8700/mm”, with 76% neutrophils, 13% lymphocytes and 11% monocytes differential count. Hemoglobin was 9.0 g/d1 and platelet count was 251 000/mm3. No irregular antibodies were identified. Continuous intravenous infusion of ritodrine at 100 pg/min was begun on the day of admission, and dosage of ritodrine was increased gradually over 4 days to 300 pg/min. From the 8th to the 21st day after admission, sodium ferrous citrate was also administered for anemia. White blood cell count began to decrease at 26 weeks gestation (about 10 days after the start of ritodrine therapy). At 28 weeks gestation (25 days after the start of ritodrine therapy), the dosage of ritodrine was increased to 400 pg/min and continuous intravenous infusion of MgSO, at 1.0 g/h was begun because of frequent uterine contractions. On increasing the dosage of ritodrine, the patient and her husband were given the explanation about the side effects of ritodrine [4-61, and gave us informed consent to its high infusion rate (> 350 pg/min) [4] because fetal survival rate could increase with progress of pregnancy. An indomethacin suppository had also been administered three times. White blood cell count at 28 weeks gestation was 15001 mm3, 1% neutrophils, 61% lymphocytes and 35% monocytes. Hemoglobin was 10 g/dl, and platelet count was 419 OOO/mm’.. She also

330

Muro Pt ul.

agranulocytosis that might take her life. On the same day, she was transvaginally delivered of two female infants weighing 1505 g and 1248 g. Immediately after the birth, she received a transfusion of 400 ml red blood cells for atonic bleeding. Four days after the cessation of tocolysis, white blood cell count rose to 4700/mm3, 2% neutrophils and 44% immature granulocytes, and the number of neutrophils and immature granulocytes increased rapidly thereafter. Seven days after the cessation of tocolysis, white blood cell count increased to 35 800/mm3, 33% segmental neutrophils, 12% banded neutrophils, and 44% immature granulocytes. Twenty-three days after the cessation of tocolysis, white blood cell count decreased to 6200/mm3, with 65% segmental neutrophils, 0% banded neutrophils and 0% immature granulocytes. The symptoms and signs of agranulocytosis improved in accordance with the rise in white blood cell count. The clinical course described above is outlined in Fig. 1.

developed a fever of 39.O”C, severe general of GOT and GPT, fatigue, elevation erythema, pharyngalgia, and an ulcer around the mouth. Antibody titers to EB virus and TORCH test were negative. For prophylaxis against infection, she was isolated in a semiaseptic room and received ampicillin (ABPC), gentamicin (GM), and fosfomycin (FOM) antibiotic therapy. Bone marrow examination at 30 weeks gestation (37 days after the start of ritodrine therapy) revealed absence of erythroblasts and only granuloblasts; megakaryoblasts could be identified. White blood cell count had fallen to 300/mm3, 1.0% neutrophils, 8 1% lymphocytes, 17% monocytes, 1% eosinophils, and 0% basophils. Therapy with methylprednisolone sodium succinate, cefazolin (CEZ), amikacin sulfate (AMK), and immunoglobulin was started. At 30 weeks and 5 days gestation (38 days after the start of ritodrine therapy), continuous infusion of ritodrine was discontinued because it was suspected of inducing

Globulin

Sodium Ferrous Citrate CFIX

ABPC+GM

FOM

Methylprednisolone Sodium Succinate DIV.

CEZ+AMK

E F

-

White Blood Cell

.*._.

Immature Granulocyte

Transfusron of RBC. Indomethacin(5Omg)SUP. 1

1

1

-4OOfig/min. R:rtodrine Hydrochloride DIV.

25

*

26

27

29

26

30

0

10

5

15

20

Pnstoartal days

Fig. 1.

Relationships

between drug administration

the white blood cell count gradually normal limits. ABPC,

Inr J Gynetal

ampicillin:

Obsrrf 36

regimens and changes in white blood cell count. After administration

began to decrease. After the cessation of ritodrine administration,

GM.

gentamicin;

FOM.

fosfomycin;

CEZ,

cefazolin;

and AMK,

of ritodrine.

it increased rapidly to within

amikacin

sulfate.

Rirodrine-induced

Discussion Our patient showed slow progressive leukopenia during continuous intravenous infusion of ritodrine at 300 &min with the administration of no other drugs except sodium ferrous citrate, as well as typical agranulocytosis with high fever, elevation of GOT and GPT, general fatigue, erythema, pharyngalgia, and an ulcer around the mouth. Furthermore, after the cessation of ritodrine, white blood cell count increased rapidly and the symptoms and signs improved. This clinical course suggests that the agranulocytosis was induced by ritodrine. The drugs that induce agranulocytosis only in some persons due to hypersensitivity reaction or metabolic disorder are divided into two classes [5], one showing rapid leukopenia due to non-dose-related toxic reaction and peripheral destruction of leukocytes, and the other showing slow progression of leukopenia due to dose-related toxic reaction and suppression of DNA synthesis of myelocytes. There has been only one case reported in the world literature of leukopenia with neutropenia suspected to have been induced by ritodrine, that reported by Wang et al. [3]. They considered that the pathophysiological mechanism was a non-dose-related toxic action. In our case, 13 days after the start of ritodrine therapy, the white blood cell count began to gradually decrease. The clinical course indicates that the leukocytopenia was probably induced by dose-related toxic reaction. Bone marrow examination revealed the and erythroblasts only presence of

ugrumdocytosis

331

megakaryoblasts, and a few granuloblasts were identified. Five days after the cessation of tocolysis, many immature granulocytes were identified in blood, and segmented neutrophils were subsequently identified. Microscopic examination of bone marrow and blood samples indicated that the neutropenia might be induced by a cell loss maturation process of myelocytes. Though the exact pathophysiological mechanism is not clear, it is suspected that agranulocytosis is induced when a large quantity of ritodrine is administered to persons having a specific constitution. References 1

lngemarsson 1: Pharmacology of tocolytic Obstet Gynecol II: 337. 1984.

2

Ben-Shlomo I, Zohar S, Marmor A, Blondheim DS et al: Myocardial ischemia during intravenous ritodrine treatment: is it so rare?. Lancet 18: 917. 1986. Wang-Cheng R, Davidson BJ: Ritodrine-induced

3 4

5

6

agents.

Clin

neutropenia. Am J Obstet Gynecol 154: 924, 1986. Merkats IR. Gyves MT: Premature labor. In: Current Therapy in Obstetrics and Gynecology 2 (ed EJ Quilligan). p 21. WB Saunders, Philadelphia, 1983. Lee GR, Boggs DR: Agranulocytosis and infectious mononucleosis. In: Clinical Hematology (ed MM Wintrobe), p 1215. Lea and Febiger. Philadelphia, 1967. Taslimi MM, Sibai BM. Amon E. Taslimi CK et al: A national survey on preterm 160: 13.52, 1989.

labor.

Am J Obstet

Gynecol

Address for reprints: H. Shone Department of Obstetrics and Gynecology Saga Medial School S-1-1, Nabeshima Saga, 849, Japan

Case Report