A possible relationship between abortions and placental embolism in pregnant rabbits given human granulocyte colony-stimulating factor.
Developmental toxicity studies were conducted in rats and rabbits with a human G-CSF derivative (NTG). As reported for G-CSF, increases in abortions and fetal mortality were observed in rabbits, but not in rats given NTG. Histopathological examination of the rabbit placenta revealed accumulation of neutrophils in vessels and necrosis of the tissues surrounding these vessels. To assess the mechanism of abortion and fetal death in rabbits given G-CSF, 125I-labeled NTG was given intravenously on Day 18 of pregnancy after repeated administration of cold NTG on Days 6 through 17 of pregnancy, and the feto-maternal distribution of radioactivity was examined. In a rabbit given 20 micrograms/kg, high radioactivity was observed in the endometrium, placenta, and some parts of the decidua at 6 hr when the concentration of radioactivity in maternal blood had already decreased. At 24 hr after administration of 200 micrograms/kg NTG, high radioactivity was still detected in parts of the maternal placenta. These patterns of distribution suggest that embolism occurred in parts of the uterus and placenta which might have caused congestion. Radioactivity in the TCA precipitates in the fetus was low, suggesting that NTG does not readily transfer to the fetus. These results strongly suggest that neutrophils accumulated in the vessels of placenta and induced embolism leading to abortions and fetal mortality in the rabbits given G-CSF.
Pharmaceutical Research and Development Division, Kyowa Hakko Kogyo Co., Ltd., 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo 100-8185, Japan.
Y
Y
Kato
T
T
Kuwabara
T
T
Itoh
M
M
Hiura
A
A
Hatori
A
A
Shigematsu
T
T
Hara
D000042:Absorption; D000818:Animals; D001345:Autoradiography; D004617:Embolism / Q000139:chemically induced*; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D010920:Placenta / Q000098:blood supply / Q000187:drug effects*; D011247:Pregnancy; D011817:Rabbits
D016179:Granulocyte Colony-Stimulating Factor; C072115:nartograstim