mercaptopurine and Fetal-Death

Topics: Alkylating Agents; Aminopterin; Animals; Antimetabolites; Antineoplastic Agents; Busulfan; Chlorambucil; Choriocarcinoma; Colchicine; Female; Fetal Death; Folic Acid Antagonists; Gestational Age; Humans; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Pregnancy; Pregnancy Complications; Urethane; Vinblastine

Topics: Asphyxia; Blood Transfusion, Intrauterine; Child; Cyclophosphamide; Erythroblastosis, Fetal; Female; Fetal Death; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Infant, Newborn, Diseases; Leukemia; Medical Records; Mercaptopurine; Methotrexate; Prednisolone; Pregnancy; Transposition of Great Vessels; Vincristine

The placenta secures the embryo and fetus to the endometrium and releases a variety of steroid and peptide hormones that convert the physiology of a female to that of a pregnant female. Chemical-induced alteration or deviation of placental function in the maternal and extraembryonic tissue can ultimately lead to pregnancy loss, congenital malformation and fetal death. The 6-mercaptopurine (6-MP), an anti-leukemic drug, is known to produce undesired effects on some organs, then the placenta/embryo toxicity of 6-MP was investigated in pregnant rats given 60 mg/kg with two intraperitoneal injections on gestation days (GD) 11 and 12. The rats were sacrificed and their placentas were collected on GD13 or 15. On GD15 small and limb-defected embryos were found in the 6-MP-treated rats. Placental weights were significantly reduced on GD15, as well as a reduced number of cells was detected in the labyrinth zone with both the labyrinth and basal zones having thinned. Cleaved caspase-3-positive cells increased in number in the labyrinth zone, while in the basal zone, glycogen cells reduced with cytolysis. The number of spongiotrophoblasts and trophoblastic giant cells also increased by 6-MP treatment. The 6-MP-treatment resulted in the increased xanthine oxidase (Xdh) expression in the placenta, which gene is related to the ischemic condition of tissues. These data suggest that apoptosis of the labyrinth zone cells may lead to decreased materno-fetal exchange. Moreover, subsequent ischemia in the placental tissue may occur and induce Xdh expression.

Topics: Animals; Apoptosis; Caspase 3; Female; Fetal Death; Gene Expression Regulation, Developmental; Mercaptopurine; Organ Size; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Xanthine Oxidase

In order to investigate the effect of placental size on fetal intrauterine growth retardation (IURG), we examined the morphology and alterations in the expression of glucose transporter in the placentas of rats exposed to 6-mercaptopurine (6-MP). 6-MP was administered orally at 0 and 60 mg/kg/day on gestation day (GD) 9, 11, 13 or 15, and the placentas were sampled on GDs 17 and 21. The main findings in the treated groups were small placenta caused by mitotic inhibition and apoptosis, fetal resorption and IUGR with or without some malformations. The most sensitive period to 6-MP-induced fetal mortality was found to be in the GD9-treated group, and the small placenta and fetal abnormalities in the GD11-treated group, respectively. However, the litters in a quarter of the dams with the treatment on GD 11 had no fetotoxicity despite 25% decline in the placental weight. Histopathologically, the expression of glucose transporter GLUT3 was increased in the trophoblastic septa in all treated groups, particularly remarkable with proliferation of trophoblasts in the above litters, where the fetal-placental weight ratio was increased. Thus, we consider that the normal fetal growth and development can be maintained caused by adaptive change, even if the placental weight decreased by approximately 25% in 6-MP exposed rats.

Topics: Abnormalities, Drug-Induced; Animals; Apoptosis; Female; Fetal Death; Fetal Growth Retardation; Fetal Weight; Gestational Age; Glucose Transport Proteins, Facilitative; Mercaptopurine; Organ Size; Placenta; Pregnancy; Rats; Rats, Inbred Strains; Teratogens

6-Mercaptopurine (6-MP) has proven efficacy in the therapy of inflammatory bowel disease. Its teratogenicity is demonstrated in animal studies when used at very high doses, whereas human data suggest that 6-MP at maintenance doses is safe. We report the outcome of 72 pregnancies in patients with inflammatory bowel disease who were previously treated with 6-MP with three different doses of 50, 75, and 100 mg/d, for a median duration of 18 months, along with long-term follow-up of the children.. We have compared the outcome of pregnancies and development of the offspring in the following two groups: group 1, patients with inflammatory bowel disease who conceived 6 months to 22 years after stopping 6-MP (median 72 months); and group 2, patients with inflammatory bowel disease who never received 6-MP prior to conception. All pregnancies were evaluated in terms of outcome: live full-term birth, premature delivery, stillbirth, spontaneous abortion, ectopic pregnancy, and therapeutic dilatation and curettage. Data on children were obtained regarding birth weight, congenital anomalies, and development.. Group 1 included 72 pregnancies carried by 29 women. There were 51 live births (4 premature), 16 spontaneous abortions, 1 stillbirth, 2 therapeutic abortions due to abnormal amniocentesis, and 2 ectopic pregnancies. The total incidence of fetal loss was 29.2%. In group 2, 75 women had 140 pregnancies resulting in 120 live births (8 premature), 18 spontaneous abortions, and 2 stillbirths. There were no cases of ectopic pregnancies or abnormal amniocentesis. The total incidence of fetal loss was 14.3%. There was no increase in the incidence of developmental defects when the mothers had been treated with 6-MP prior to pregnancy.. The incidence of fetal loss is higher in women with inflammatory bowel disease who had been previously treated with 6-MP compared with those who had not. Whether this was related to the older age at conception in 6-MP group, longer duration of disease, initially more severe disease, or use of 6-MP we cannot tell.

Topics: Abortion, Spontaneous; Adult; Case-Control Studies; Child Development; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Embryonic and Fetal Development; Female; Fetal Death; Humans; Infant, Newborn; Infant, Premature; Inflammatory Bowel Diseases; Mercaptopurine; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prevalence; Probability; Reference Values; Risk Assessment

Two patients with acute promyelocytic leukemia (APL) in 2nd and 3rd trimester of pregnancy are reported on. Case 1: 38-year-old female consulted our hospital because of bleeding tendency and pancytopenia in April, 1988. She was diagnosed as having APL with disseminated intravascular coagulopathy (DIC) and was found to be in the 14th week of gestation. Combined chemotherapy (BHAC-DMP) including the total dose (440 mg) of daunorubicin (DNR) resulted in intrauterine fetal death at 19 weeks of gestation. The fetus was severely anemic and the bone marrow was hypoplastic. Case 2: A 27-year-old female was diagnosed as having APL with DIC at 29 weeks of gestation. BHAC-DMP including 440 mg DNR achieved complete remission. At 35 weeks of gestation, she delivered a normal infant by Caesarean section. The child had normal hematological findings and showed normal growth. Both cases developed APL accompanied by DIC during pregnancy and were treated with a similar regimen including high dose of anthracyclines. Case 2 treated in the late period of gestation delivered a normal infant, while fetal death resulted in case 1, treated in the early period of gestation. We reviewed the literature regarding chemotherapy using anthracyclines during pregnancy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Embryonic and Fetal Development; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Prednisolone; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Complications, Neoplastic

Short term drug toxicities were investigated using cultures of mouse embryos in the early stage of development. These embryos were collected at the two- or eight-cell stage. They were exposed to bleomycin (B1) or 6-mercaptopurine (MP) for 24 hr, thereafter, they were grown in BMOC-3 medium without these agents until the blastocyst stage. Total culturing period was 72 hr for the two-cell embryos and 48 hr for the eight-cell embryos. At the end of the culture periods, the number of cells, mitotic index and frequencies of sister chromatid exchange in these embryos after these exposures were unaltered. However, the death rate of embryos was elevated by the exposure to either B1 or MP. These agents are regarded as non-carcinogenic mutagens; therefore, it is suggested that these compounds are lethal to the embryos through an induction of mutation.

Topics: Animals; Bleomycin; Cell Count; Cleavage Stage, Ovum; Culture Techniques; Female; Fetal Death; Mercaptopurine; Mice; Mice, Inbred ICR; Mitotic Index; Pregnancy; Sister Chromatid Exchange

The implantation traces of early embryonal death and abortion in rats induced by some drugs were studied. Early embryonal death and abortion were caused by intraperitoneal injection of 15 mg/kg of busulfan on the 7th day of gestation or 40 mg/kg of 6-mercaptopurine on the 7th and 8th day of gestation. The observation period and staining of the implantation traces were investigated. Early dead embryos and placentas were delivered between the 20th and 24th day of gestation. These were eaten by the dams. The implantation traces of abortion or early embryonal death, and those of normal delivery were able to be identified up to the 120th day and 500th day after extraction, respectively. The implantation traces of abortion were smaller in the three experimental groups. All kinds of implantation traces were stained distinctly with 10% ammonium sulfide, 0.2% sodium hydroxide and 2% potassium ferrocyanide. In this staining method, sodium hydroxide has an excellent effect on the staining of implantation traces. Specimens washed in water after being stained with sodium hydroxide and fixed in formalin can be preserved without discoloration for a long period of time.

Topics: Abortion, Spontaneous; Animals; Busulfan; Embryo Implantation; Female; Fetal Death; Gestational Age; Mercaptopurine; Pregnancy; Rats; Rats, Inbred Strains; Staining and Labeling; Time Factors; Uterus

Hybrid (101 X C3H)F1 male mice were given [3H]thymidine intraperitoneally, and 1 h later 150 mg/kg 6-mercaptopurine in 0.03 N NaOH. Autoradiography of testis sections showed that the rate of spermatogenesis was not altered, and the time of appearance of labeled spermatozoa in the ejaculate indicated that 6-mercaptopurine also had no effect on minimum sperm transport time. Labeled spermatozoa persisted in the ejaculate for a longer interval in 6-mercaptopurine-treated males than in controls, most likely as a result of oligospermia. Combined treatment with 150 R X-rays and 150 mg/kg 6-mercaptopurine gave an additive effect and demonstrated conclusively that the peak incidence of dead implants observed at 30.5 - 35.5 days can be attributed to cells treated as preleptotene spermatocytes and must result from genetic damage that is not cytologically detectable; previous work has shown that chromatic and isochromatid breaks at diakinesis-metaphase I occurred only on days 14 and 15 after 150 mg/kg 6-mercaptopurine. From the present experiments it is clear that these aberrations are not related to the dominant lethality at 30.5 - 35.5 days.

Topics: Animals; Cell Cycle; Cell Survival; Chromosome Aberrations; Female; Fetal Death; Male; Mercaptopurine; Mice; Oligospermia; Pregnancy; Spermatocytes; Spermatogenesis; Spermatozoa; Time Factors

Topics: Animals; Carcinogens; Chemical Phenomena; Chemistry; Drug Interactions; Female; Fetal Death; Humans; Male; Mercaptopurine; Mice; Mutagenicity Tests; Neoplasms, Experimental; Pregnancy; Rats; Reproduction; Teratogens

The immunosuppressive drug 6-mercaptopurine is embryotoxic in mice. Of the surviving female offspring of mice treated with low doses of 6-mercaptopurine during pregnancy, despite normal body weight and general appearance, many were either sterile or, if they became pregnant, had smaller litters and more dead fetuses as compared to offspring of mothers that had not received the drug.

Topics: Animals; Dose-Response Relationship, Drug; Female; Fetal Death; Fetus; Germ Cells; Infertility, Female; Litter Size; Mercaptopurine; Mice; Ovary; Pregnancy; Pregnancy, Animal

Topics: Abnormalities, Drug-Induced; Animals; Animals, Laboratory; Azathioprine; Bone and Bones; Female; Fetal Death; Lagomorpha; Mammals; Mercaptopurine; Mice; Pregnancy; Rabbits; Rats

Topics: Animals; Dose-Response Relationship, Drug; Embryo Implantation; Female; Fertilization; Fetal Death; Genes, Dominant; Genes, Lethal; Injections, Intraperitoneal; Male; Mercaptopurine; Mice; Mice, Inbred Strains; Pregnancy; Spermatogenesis

Topics: Animals; Dose-Response Relationship, Drug; Embryo Implantation; Embryo, Mammalian; Female; Fetal Death; Genes, Dominant; Genes, Lethal; Genetic Techniques; Male; Mercaptopurine; Mesylates; Mice; Mutation; Pregnancy; Species Specificity; Spermatogenesis; Statistics as Topic; Toxicology

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Amides; Animals; Female; Fetal Death; Fetus; Mercaptopurine; Mice; Pregnancy; Pregnancy, Animal