mercaptopurine and Abnormalities--Drug-Induced

Maintaining remission of inflammatory bowel disease (IBD) during pregnancy is critical for positive pregnancy outcomes. Conflicting data exist regarding the association between thiopurine use for IBD treatment in pregnancy and adverse pregnancy outcomes and this meta-analysis aims to clarify this association. A meta-analysis was performed of all original human studies reporting outcomes in pregnancy in patients receiving thiopurines. Nine studies satisfied the inclusion criteria and a total of 494 patients with IBD and 2,782 IBD controls were reported. When compared with healthy women, those receiving thiopurines had an increased risk for congenital malformations (RR 1.45; 95% CI 1.07-1.96; p = 0.02); however, when compared with IBD controls, there was no increased risk (RR 1.37; 95% CI 0.92-2.05; p = 0.1). These data provide support for thiopurines having a minimal risk, if any, to the fetus.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Animals; Azathioprine; Birth Weight; Case-Control Studies; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth

Inflammatory bowel disease often affects women during their reproductive years, causing management concerns for obstetricians caring for these patients during pregnancy.. Apart from methotrexate, most drugs used regularly to treat ulcerative colitis and Crohn's disease can safely be used by pregnant women. No causal relationship has been established between exposure to sulfasalazine or other 5-aminosalicylic acid drugs and the development of congenital malformations and these drugs may be used with relative safety during pregnancy and lactation. Current evidence indicates that maternal use of azathioprine and mercaptopurine is not associated with an increased risk of congenital malformations, though impaired foetal immunity, intrauterine growth retardation and prematurity are occasionally observed. Cyclosporin is not teratogenic, but may be associated with growth retardation and prematurity.. Pregnancy should be avoided in women treated with methotrexate because of its known abortifacient effects and risk of causing typical malformations. There is no actual evidence of adverse effect in pregnant women receiving Infliximab but the amount of clinical information is small. The treatment with metronidazole or ciprofloxacin for short durations appear to be safe, but there is no data about the effects of increased length of treatment as required in Crohn's disease remains unknown. Control of disease activity before conception and during pregnancy is critical to optimise both maternal and foetal health. A multidisciplined approach involving both obstetrician and gastroenterologist and education about pregnancy are essential components of the treatment of any young women with IBD.

Topics: Abnormalities, Drug-Induced; Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Azathioprine; Breast Feeding; Contraindications; Cyclosporine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Maternal Nutritional Physiological Phenomena; MEDLINE; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Topics: Abnormalities, Drug-Induced; Adrenal Cortex Hormones; Animals; Azathioprine; Chlorambucil; Cyclophosphamide; Cyclosporine; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infertility, Female; Mercaptopurine; Methotrexate; Mice; Pregnancy; Pregnancy Complications; Rheumatic Diseases

Topics: 6-Aminonicotinamide; Abnormalities, Drug-Induced; Animals; Bone and Bones; Cartilage; Cell Division; Collagen; Embryo Implantation; Extremities; Female; Limb Deformities, Congenital; Mercaptopurine; Mesoderm; Mice; Osteogenesis; Proteoglycans; Teratogens; Time Factors; Vitamin A

In a survey of the literature the teratogenic effects of radiation and some drugs are discussed. Teratogenicity is proved for thalidomide, aminopterin, busulfan, cyclophosphamide, chlorambucil, mercaptopurin and diphenylhydantoin, trimethadione and warfarin. After the thalidomide-tragedy drug-induced malformations of the embryo are extremely rare, whereas malformations due to alcohol are rather frequent. Own experiences with more than 70 patients with alcoholembryopathy are reported. Nicotin seems not to be teratogenic, but due to nicotin the perinatal mortality is elevated. The questionable teratogenic effects of Heroin and LSD are discussed.

Topics: Abnormalities, Drug-Induced; Aminopterin; Busulfan; Chlorambucil; Cyclophosphamide; Ethanol; Germany, West; Heroin Dependence; Humans; Infant Mortality; Infant, Newborn; Lysergic Acid Diethylamide; Mercaptopurine; Nicotine; Phenytoin; Radiation Injuries; Teratogens; Thalidomide; Trimethadione; Warfarin

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Antineoplastic Agents; Busulfan; Carcinogens; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Female; Heart Diseases; Humans; Lung Diseases; Male; Menstruation Disturbances; Mercaptopurine; Methotrexate; Neoplasms; Neoplasms, Radiation-Induced; Pregnancy; Radiotherapy; Urinary Bladder Diseases

Topics: Abnormalities, Drug-Induced; Alkylating Agents; Allopurinol; Alopecia; Antimetabolites; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Drug Synergism; Female; Fetus; Humans; Kidney Calculi; Kidney Diseases; Kidney Tubules; Mechlorethamine; Mercaptopurine; Neoplasms; Pregnancy; Pregnancy Complications; Uric Acid; Vincristine

Topics: Abnormalities, Drug-Induced; Animals; Antigens; Antineoplastic Agents; Azathioprine; Chemical Phenomena; Chemistry; DNA; Drug Interactions; Female; Humans; Immunosuppressive Agents; Lethal Dose 50; Lymphocytes; Mercaptopurine; Methotrexate; Mice; Pregnancy; Rabbits; Rats; Transplantation Immunology

Topics: Abnormalities, Drug-Induced; Alkylating Agents; Animals; Antineoplastic Agents; Carcinogens; Cyclophosphamide; Embryo, Mammalian; Female; Fetus; Fluorouracil; Gestational Age; Hydroxamic Acids; Hydroxyurea; Mannomustine; Mechlorethamine; Mercaptopurine; Nitroso Compounds; Pregnancy; Rats; Urethane

Several studies have demonstrated a favourable safety profile for thiopurine use for inflammatory bowel disease (IBD) during pregnancy. We performed a study in pregnant patients with IBD who were using thiopurines, in order to determine the influence of pregnancy on thiopurine metabolism and to assess intrauterine exposure of the fetus to thiopurines.. Female patients with IBD receiving steady-state thiopurines and planning a pregnancy were prospectively enrolled. 6-Thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations were determined, combined with routine laboratory tests, before, during and after pregnancy. Thiopurine metabolites were measured in umbilical cord blood immediately after delivery.. Thirty patients who were using azathioprine (28 patients, median dose 1.93 mg/kg) or mercaptopurine (two patients, doses 1.32 and 0.94 mg/kg) were included. During pregnancy, median 6-TGN decreased over time (p=0.001). while 6-MMP increased, without causing myelotoxicity or hepatotoxicity. After delivery, both 6-TGN and 6-MMP levels returned to preconception baseline levels. Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). No 6-MMP was detected in the newborns, except one born with pancytopenia and high alkaline phosphatase activity; the mother of this infant had severe pre-eclampsia. All infants had normal Apgar scores, but 60% had anaemia at birth. No major congenital abnormalities were observed.. Pregnancy has a major effect on maternal thiopurine metabolism. In utero the unborn child is exposed to 6-TGN, but not to 6-MMP. Sixty per cent of the infants were born with anaemia, which raises the question whether infants should be tested for possible anaemia immediately after birth.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Anemia, Neonatal; Azathioprine; Biomarkers; Female; Fetal Blood; Follow-Up Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Mercaptopurine; Middle Aged; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Thionucleotides; Treatment Outcome; Young Adult

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

Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of women with IBD who have been exposed to thiopurines.. 215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C).. Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome.. The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.

Topics: Abnormalities, Drug-Induced; Adult; Birth Weight; Cohort Studies; Female; France; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Maternal-Fetal Exchange; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Treatment Outcome; Young Adult

I have several patients with inflammatory bowel disease (IBD) who are pregnant or planning pregnancies. What information can I give them regarding the possible effects of IBD on pregnancy and the medications used to treat IBD during pregnancy?. Women with IBD appear to be at increased risk of giving birth prematurely, having low-birth-weight infants, and having cesarean sections. Neither 5-aminosalicylic acid nor sulfasalazine has been found to increase the rate of major malformations, fetal mortality, or morbidity. There is conflicting evidence regarding the use of corticosteroids and azathioprine and 6-mercaptopurine. There are limited data on the use of infliximab during pregnancy, although no pattern of defects or complications has been reported to date.

Topics: Abnormalities, Drug-Induced; Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Infective Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk; Sulfasalazine

Topics: Abnormalities, Drug-Induced; Crohn Disease; Female; Fetus; Humans; Immunosuppressive Agents; Mercaptopurine; Pregnancy; Pregnancy Complications

Data on birth outcome after exposure to azathioprine or mercaptopurine during pregnancy is sparse.. To examine the risk of adverse birth outcome among newborns of women exposed to azathioprine or mercaptopurine during pregnancy.. Data on drug use and births were obtained from Danish population registries. We included 76 exposed pregnancies in 69 women. Of these, we used 64 pregnancies exposed 30 days before conception or during the first trimester to examine the risk of congenital abnormalities, and 65 pregnancies exposed during the entire pregnancy to examine preterm birth and low birth weight at term. Their birth outcomes were compared with outcomes among women who did not fill prescriptions for azathioprine or mercaptopurine during pregnancy.. Azathioprine- or mercaptopurine-exposed women had a higher risk of adverse birth outcomes than unexposed controls. However, when the comparison was limited to newborns of women with the same types of underlying disease, relative risks for spontaneous and induced preterm birth, low birth weight at term, and congenital abnormalities were 1.1 (95% CI: 0.5-2.4), 4.0 (95% CI: 1.5-10.8), 1.7 (95% CI: 0.3-8.7) and 1.1 (95% CI: 0.5-2.9), respectively.. Our results suggest that adverse birth outcomes were caused by the underlying disease rather than by use of azathioprine or mercaptopurine.

Topics: Abnormalities, Drug-Induced; Azathioprine; Cohort Studies; Denmark; Female; Humans; Immunosuppressive Agents; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Male; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects

Immunosuppressive therapy with azathioprine and mercaptopurine is commonly used in patients with various chronic diseases. The few existing data on the reproductive safety of these drugs after paternal use before conception are inconclusive.. To examine the risk of congenital abnormalities in children fathered by men exposed to azathioprine or mercaptopurine before conception.. This was a Danish population-based cohort study, based on data from the Prescription Database, the Medical Birth Registry and the Hospital Discharge Registry of North Jutland County, Denmark. Fifty-four exposed pregnancies, in which the father filed a prescription for azathioprine or mercaptopurine (between 1 January 1991 and 31 December 2001) before conception, were included. The controls comprised 57 195 pregnancies with no paternal azathioprine or mercaptopurine use.. Four children with congenital abnormalities (underlying paternal diseases: glomerulonephritis and severe skin disease) were found in 54 exposed pregnancies (7.4%), compared with 2334 (4.1%) in controls. The adjusted odds ratio for congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine was 1.8 (95% confidence interval, 0.7-5.0).. Our data may indicate that paternal use of azathioprine or mercaptopurine before conception is associated with an increased risk of congenital abnormalities. However, more data are needed to determine whether the association is causal.

Topics: Abnormalities, Drug-Induced; Azathioprine; Cohort Studies; Denmark; Humans; Immunosuppressive Agents; Infant, Newborn; Male; Mercaptopurine; Paternal Exposure; Risk Factors

Topics: Abnormalities, Drug-Induced; Azathioprine; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Paternal Exposure; Spermatozoa

Data on the safety of azathioprine and mercaptopurine during pregnancy are very sparse.. To examine the risk of adverse birth outcomes in women who took up prescriptions for azathioprine or mercaptopurine during pregnancy.. This is a Danish cohort study based on data from a population-based prescription registry, the Danish Birth Registry and the Hospital Discharge Registry. To examine the risk of congenital malformations, we included nine pregnancies exposed 30 days before conception or during the first trimester. To examine perinatal mortality, pre-term birth and low birth weight, we included 10 pregnancies exposed during the entire pregnancy. Eleven different exposed women were included in the study. Outcomes were compared with those of 19 418 pregnancies in which no drugs were prescribed to the mothers.. Fifty-five per cent of the exposed women had inflammatory bowel disease and 45% other diseases. Adjusted odds ratios for congenital malformations, perinatal mortality, pre-term birth and low birth weight were 6.7 (95% confidence interval, 1.4-32.4), 20.0 (2.5-161.4), 6.6 (1.7-25.9) and 3.8 (0.4-33.3), respectively.. Our results suggest that there is an increased risk of congenital malformations, perinatal mortality and pre-term birth in children born to women treated with azathioprine or mercaptopurine during pregnancy. More data are needed to determine whether the associations are causal or occur through confounding.

Topics: Abnormalities, Drug-Induced; Azathioprine; Cohort Studies; Denmark; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Registries; Risk Factors

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Crohn Disease; Female; Humans; Infant, Newborn; Male; Mercaptopurine; Pregnancy; Pregnancy Complications; Teratogens

Topics: Abnormalities, Drug-Induced; Animals; Antimetabolites, Antineoplastic; Azathioprine; Cricetinae; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Mice; Patient Education as Topic; Pregnancy; Rabbits; Rats; Teratogens; Zinc

Topics: Abnormalities, Drug-Induced; Fathers; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Risk Factors

The outcomes of pregnancies after maternal use of 6-mercaptopurine (6-MP) for inflammatory bowel disease (IBD) during pregnancy have been reported, but data are lacking for outcomes when the fathers use this drug.. Subjects were male patients with IBD seen at one center between 1970 and 1997. Patients and their wives were interviewed. Group 1 comprised pregnancies fathered by men who were taking 6-MP. This group was further subdivided into those conceived within 3 months of 6-MP use and those conceived at least 3 months after 6-MP was stopped. Group 2 comprised pregnancies fathered by men with IBD, similar in characteristics to group 1, who had not taken 6-MP before fertilization. Information was collected regarding the fathers, the mothers, and the pregnancies, as well as the health of the children, in a historical cohort study.. There were 50 pregnancies in group 1 (13 in 1A and 37 in 1B) and 90 pregnancies in group 2. Four of the 13 pregnancies in group 1A were associated with complications. There were two spontaneous abortions, and two congenital anomalies including a missing thumb in one and acrania with multiple digital and limb abnormalities in the other. Risk of complications was significantly increased when compared with group 1B (p < 0.013) and group 2 (p < 0.002).. The incidence of pregnancy-related complications was significantly increased when the fathers used 6-MP within 3 months of conception.

Topics: Abnormalities, Drug-Induced; Adult; Drug Administration Schedule; Fathers; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pregnancy; Pregnancy Outcome

Topics: Abnormalities, Drug-Induced; Female; Fertilization; Humans; Immunosuppressive Agents; Incidence; Infant, Newborn; Inflammatory Bowel Diseases; Male; Mercaptopurine; Paternal Exposure; Pregnancy; Pregnancy Outcome; Risk Factors

In 108 fetal mice and 67 rat fetuses the normal development of the temporomandibular joint was initially explored. Then malformations of the splanchnocranium were induced and studied histologically in 287 newborn rats and 67 mice. These animals had been delivered by caesarean section after treating the pregnant dams with one of 6 different teratogens. Finally, anomalous temporomandibular joints in 53 patients were analyzed radiographically and compared to the findings made in the above mentioned laboratory animals. Most malformations of the temporomandibular region detected were found to be embryopathies. They all fit into a new teratogenic order that was established by comparing the abnormal to the normal development of the structures involved.

Topics: Abnormalities, Drug-Induced; Animals; Cyclophosphamide; Female; Glycine; Humans; Hydroxamic Acids; Infant, Newborn; Mercaptopurine; Methylnitrosourea; Mice; Mice, Inbred Strains; Pregnancy; Procarbazine; Rats; Rats, Sprague-Dawley; Temporomandibular Joint; Teratogens

A 29-year-old pregnant woman diagnosed with acute lymphocytic leukemia maintained remission with daily cyclophosphamide and intermittent prednisone treatment. She delivered a male twin with multiple congenital abnormalities who was diagnosed with papillary thyroid cancer at 11 years of age and stage III neuroblastoma at 14 years of age. The female twin was unaffected and has exhibited normal development to date. First trimester exposure to cyclophosphamide has been associated with major malformations. Metabolites of cyclophosphamide have been demonstrated to be teratogens and carcinogens in animals. Differences in placental or fetal hepatic cytochrome P-450 may account for the variability in response between the twins. In addition, disparity between the twins may be the result of differences in metabolite inactivating enzymes present either in fetal liver or placenta. The risk of second malignancies caused by alkylating agents such as cyclophosphamide has been well documented in adults and children but to the best of our knowledge this is the first description of transplacental second cancer.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adrenal Gland Neoplasms; Adult; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Papillary; Cyclophosphamide; Diseases in Twins; Female; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Mercaptopurine; Neuroblastoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Exposure Delayed Effects; Thyroid Neoplasms; Time Factors; Twins, Dizygotic; Vincristine

The relationship between 6-mercaptopurine-induced alterations in mineral metabolism and the teratogenic effects of the drug were investigated. Pregnant Sprague-Dawley rats were fed diets containing 4.5, 100, or 1,000 micrograms Zn per 1 g diet. On day 11 of gestation, dams were given intraperitoneal injections of 6-mercaptopurine (27.5 mg/kg). At term, dams fed the 1,000-micrograms Zn per 1 g diet showed fewer drug-induced deleterious effects on reproduction and embryogenesis than did those fed lower levels of zinc. Mineral analysis of maternal and fetal tissues revealed pronounced effects of 6-mercaptopurine on metabolism of zinc, copper, iron, calcium, and magnesium. The results of this study indicate that 6-mercaptopurine teratogenesis may be due in part to drug-induced changes in mineral metabolism.

Topics: Abnormalities, Drug-Induced; Animals; Calcium; Copper; Female; Fetus; Iron; Magnesium; Maternal-Fetal Exchange; Mercaptopurine; Minerals; Organ Size; Placenta; Pregnancy; Rats; Tissue Distribution; Zinc

Rat embryos in the organ formation phase (days 9.5-11.5 post coitum) were cultivated in pure rat serum in the presence of an Aroclor 1254 pretreated liver microsomal preparation (S9-mix). Various concentrations of the immunosuppressive drugs azathioprine (AZ), 6-mercaptopurine (MP), methotrexate (MTX) or cyclosporin A (CS-A) were added at the beginning of the culture period. Forty-eight hours later, malformations were observed in the AZ, MP and MTX treated embryos at concentrations as low as 1 microgram/ml, 1.8 micrograms/ml and 0.05 microgram/ml, respectively. This indicates that these drugs have a direct effect on embryonic development. They selectively affected the rhombencephalic and telencephalic brain regions. Other malformations were seen in the caudal trunk, the heart and forelimb regions, and in the vesicular structures. It is suggested that the similarity of the pharmacological action of these drugs, that is, the DNA de novo synthesis inhibition, was the cause of the comparable types of malformations observed. Higher AZ, MP and MTX concentrations caused concentration-dependent increases in the types and incidences of malformations, as well as inhibited overall growth and differentiation. CS-A, a new type of immunosuppressant agent, had no effect on the morphogenetic events at the concentrations tested. These results are generally in agreement with the literature data, indicating that AZ, MP and MTX induce malformations in whole-animal systems, whereas CY-A does not. When AZ and MTX were assayed in the rat species in vivo, on the other hand, embryolethalities and retardations, but few malformations, were observed. The possibility of controlled exposure in vitro may, therefore, offer the advantage that clearer distinctions between embryolethal and teratogenic effects can be made.

Topics: Abnormalities, Drug-Induced; Animals; Azathioprine; Brain; Cyclosporins; Dose-Response Relationship, Drug; Female; Male; Mercaptopurine; Methotrexate; Organ Culture Techniques; Pregnancy; Rats; Rats, Inbred Strains

An infant born with preaxial polydactyly to a mother taking azathioprine throughout pregnancy is described. Experimental studies in animals reveal a teratogenic role for azathioprine and its main metabolite, 6-mercaptopurine. The skeletal system appears to be the primary tissue target for such action of these drugs. Although no direct cause-effect relationship can be established from the single case presented, the similarity of this anomaly to experimental azathioprine teratogenesis suggests the necessity for further surveillance.

Topics: Abnormalities, Drug-Induced; Adult; Animals; Azathioprine; Female; Fingers; Humans; Infant, Newborn; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Pregnancy; Pregnancy Complications; Rats

The long-term development of the CNS and its fundamental processes represent the basis of the high sensitivity of neural structures also during postnatal phases of development. Successive teratological rows of the CNS can be produced by application of different teratogenic substances at different times of development. Different teratogenic agents produce different malformations at the same day of development. Each teratogenic substance cause agent specific effects. Histological methods reveal the changing sensitivity of neural structures after application of special teratogenic agents at different times of development.

Topics: Abnormalities, Drug-Induced; Animals; Central Nervous System; Cyclophosphamide; Gestational Age; Mercaptopurine; Rats; Teratogens; Trypan Blue

Pregnant hamsters were given varying doses of 6-mercaptopurine (6MP) at various times during gestation. The fetuses were examined for both gross and histological malformations which showed that the toxic and teratogenic effects of 6MP were dose and time dependent. The most severe gross malformations induced by 6MP were cleft palate, micrognathia and agnathia, microglossia, short limbs, and gut herniation. Grossly normal appearing fetuses, greated during late gestation, showed malformations at the tissue and cellular level. The effects of 6MP in hamster was compared with other species, and with other growth-supressive agents, and it was deduced that the teratogenicity of 6MP is species and tissue specific. Also, it was recommended that histological observations be made an integral part of the teratological safety analysis.

Topics: Abnormalities, Drug-Induced; Animals; Cricetinae; Dose-Response Relationship, Drug; Female; Gestational Age; Mercaptopurine; Mesocricetus; Pregnancy; Teratogens

The risks of embryonic, fetal, gondal damage of cancer chemotherapy are reviewed. Contrasting with the numerous malformations seen in laboratory animals, the teratogenic risk is low in man. Methotrexate is really dangerous during the first trimester of pregnancy. In malignant haematological diseases and solid tumours, the prognosis of the disease is the essential target but the use of immuno-suppressive drugs in non-malignant diseases is hazardous before 40 years of age. All the investigations show that alkylating agents injure the gonads. Young women should be avised to use contraceptives. The future of children born after administration of anti cancer drugs is uncertain. Sterility, carcinogenic risk, mutation, teratogenetic effects in future generations cannot be ruled out.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Alkaloids; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Embryo, Mammalian; Female; Fetus; Folic Acid Antagonists; Humans; Infertility; Male; Mercaptopurine; Mice; Neoplasms; Pregnancy; Pregnancy Complications; Rabbits; Rats

The possible interaction between the level of maternal dietary zinc and the teratogenic activity of 6-mercaptopurine was investigated. Pregnant Sprague-Dawley rats were fed diets containing 9,100 or 1,000 ppm zinc from day zero of pregnancy and were given a single intraperitoneal injection of 6-MP (55mg/kg) on day 11. At term, females in the group fed 1,000 ppm zinc (a high intake) showed less pronounced effects on reproduction and embryogenesis than did those fed 9 ppm (marginally deficient) or 100 ppm (normal) zinc. Embryos examined on day 12 of gestation had similar concentrations of protein and RNA; however, the DNA content was lower and the incorporation of 3H-thymidine was greater in the drug treated groups than in non-drug treated controls. These results indicate that 6-mercaptopurine is acting to alter embryonic DNA metabolism and that high levesl of dietary zinc may ameliorate some of the deleterious effects of this drug on embryonic and maternal toxicity.

Topics: Abnormalities, Drug-Induced; Animals; Diet; DNA; Embryo, Mammalian; Female; Mercaptopurine; Pregnancy; Pregnancy, Animal; Proteins; Rats; Reproduction; RNA; Teratogens; Zinc

Pregnant Sprague-Dawley rats were fed diets containing 9 (marginal level), 100 (control level), or 1,000 (very high level) ppm zinc and were given a single intraperitoneal injection of 6-mercaptopurine (6-MP, 55 mg/kg) or an equivalent volume of carboxymethylcellulose on day 11 of gestation. Live young and their placentas were recovered at surgery on day 21 of gestation: they were weighed, measured, and placentas were examined histologically. Placentas from drug treated animals were smaller in diameter and lighter in weight than controls; however, the placentas of animals fed the 1,000 ppm zinc diet were significantly heavier than those of the other drug-treated groups. Histologically, the placentas of the 6-MP treated dams showed a highly disproportionate reduction in the labyrinthine layer with larger, less subdivided maternal sinuses than in controls, reduction of fetal vasculature, vesiculation of trophoblast nuclei, deposition of PAS positive material in the septal wall, and fibrinous degeneration of trophoblast cells. These morphological changes were reduced in placental tissues of drug treated rats given 1,000 ppm of zinc. In contrast, no placental abnormalities were observed in rats not treated with 6-MP.

Topics: Abnormalities, Drug-Induced; Animals; Diet; Female; Fetus; Mercaptopurine; Organ Size; Placenta; Pregnancy; Pregnancy, Animal; Rats; Zinc

The reproductive performance of 36 women who had been successfully treated for gestational trophoblastic tumors with multiple courses of cytotoxic agents including methotrexate, 6-mercaptopurine, actinomycin D, and 6-azauridine, between 1962 and 1972, has been studied in comparison with 36 patients who had spontaneously aborted a hydatidiform mole but received no treatment and a control group consisting of 36 women attending an antenatal clinic. The majority of patients who wanted further pregnancies following chemotherapy had one or more successful conceptions. The incidence of abnormal pregnancies in the treated group was higher than that of the control group. Similarly, there was a higher number of abnormal pregnancies in the untreated mole patients when compared with the control group. This suggests that patients who develop trophoblastic tumors tend to have a poor obstetric history and that this is not significantly worsened by chemotherapy.

Topics: Abnormalities, Drug-Induced; Antineoplastic Agents; Azauridine; Child; Child, Preschool; Dactinomycin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydatidiform Mole; Infant; Infant, Newborn; Leucovorin; Male; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications; Trophoblastic Neoplasms; Uterine Neoplasms

Topics: Abnormalities, Drug-Induced; Azathioprine; Cortisone; Cyclophosphamide; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Infertility; Male; Mercaptopurine; Methotrexate; Neoplasms; T-Lymphocytes

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Embryonic Development; Ethanol; Female; Mercaptopurine; Pregnancy; Rats; Trypan Blue

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

Fertilized eggs of single-combed White Leghorn hens were each injected through a shell window directly beneath the embryo at 70 or 96 h of incubation with 2 mg of the sodium salt of 6-MP dissolved in 0.1 M phosphate buffer, and at 11 days of incubation the embryos were examined for gross morphological abnormalities. Various gross malformations and growth retardation were found, the most frequently and severely affected structures being limbs, beak, and eyes. Treatment at 70 h caused more severe abnormalities than at 96 h, but the spectrum of defects was not very different.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Chick Embryo; Lethal Dose 50; Mercaptopurine; Teratogens; Time Factors

Wistar rats were administered single doses of 16 or 50 mg/kg 6-mercaptopurine (6-MP) on day 12 of pregnancy. Necrosis in the fetal forebrain and spinal cord was studied by light microscope 6, 12, 14, 48, 72, and 81 h and 8 days afterward. The extent of necrosis was dose dependent. The first necroses were seen after 24 h, regardless of location (brain, spinal cord) or dose; but the extent was greatest after 48 h. All necrotic cells had a typical appearance; they were ballooned and often fragmented, their nuclei were darkly colored and frequently pyknotic, and they were often karyorhexic. Necroses appeared almost exclusively at sites of beginning cellular differentiation, i.e., in the intermediate zone. In the spinal cord the ventricular zone was also necrotic and the alar plate (dorsal horn) always affected. Phagocytizing cells (macrophages) appeared in the spinal cord after 48 h and in the brain after 72 h. After 81 h all the necrotic material had been phagocytized, at which time there was a massive congestion of the extra- and intracerebral vessels. Hemorrhages appeared in defined localizations. Eight days after exposure to 16 mg/kg 6-MP fetuses no longer showed any visible deviations. Fetuses exposed to 50 mg/kg showed deviations in the cytoarchitecture of the neopallium: an extremely broadened ventricular zone, few cells in the intermediate zone, and extensive rarefaction cells in the cortical plate with no clear layer structure. In the spinal cord, cleft formations were especially noticeable in the dorsal-horn region. All fetuses showed a hydrocephalus externus after 50 mg/kg. The mechanism leading to necrosis is discussed.

Topics: Abnormalities, Drug-Induced; Animals; Brain; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Hydrocephalus; Intracranial Arteriovenous Malformations; Macrophages; Mercaptopurine; Necrosis; Phagocytosis; Pregnancy; Rats; Spinal Cord; Teratogens

Topics: Abnormalities, Drug-Induced; Animals; Cell Differentiation; Dissection; Epithelium; Extremities; Female; Mercaptopurine; Mice; Pregnancy; Purine Nucleosides

After i.p. application of 16 or 25 mg/kg, resp., 6-mercaptopurine on day 12 of gestation, numerous bone aplasias in the extremities can be demonstrated using the alizarine-red clearing method or X-ray techniques. In a few cases, however, histological examination reveals the presence of an unmineralized cartilagenous skeletal piece. The cause of this malformation is presumably the damaging of precursor cells of the osteoblasts responsible for the desmal and enchondral esteogenesis during the blastema stage. Therefore, it is to be distinguished between the true and the cartilagenous aplasias.

Topics: Abnormalities, Drug-Induced; Animals; Bone Development; Dose-Response Relationship, Drug; Extremities; Female; Fibula; Forelimb; Hindlimb; Mercaptopurine; Pregnancy; Rats; Teratogens; Tibia

Topics: Abnormalities, Drug-Induced; Animals; Bromodeoxyuridine; Disease Models, Animal; Ectromelia; Forelimb; Gestational Age; Mercaptopurine; Mice; Mice, Inbred Strains; Organ Culture Techniques; Syndactyly

Topics: Abnormalities, Drug-Induced; Adrenal Cortex Hormones; Aminopterin; Amniocentesis; Animals; Anti-Bacterial Agents; Azathioprine; Azauridine; Busulfan; Chlorambucil; Colchicine; Contraceptives, Oral; Cyclophosphamide; Diethylstilbestrol; Ethanol; Female; Fetus; Genotype; Humans; Iodine Radioisotopes; Mercaptopurine; Methotrexate; Mice; Nitrogen Mustard Compounds; Phenotype; Pregnancy; Pregnancy, Animal; Prenatal Diagnosis; Radiation Genetics; Rats; Species Specificity; Thalidomide; Tranquilizing Agents

Topics: Abnormalities, Drug-Induced; Animals; Cell Survival; Cyclophosphamide; Dactinomycin; Embryo, Mammalian; Embryonic and Fetal Development; Female; Fetus; Magnesium Deficiency; Mercaptopurine; Mice; Mice, Inbred Strains; Microscopy, Electron; Necrosis; Niacinamide; Pregnancy; Rats; Rats, Inbred Strains; Vincristine; Vitamin A

Topics: Abnormalities, Drug-Induced; Animals; Cleft Lip; Cleft Palate; Cyclophosphamide; Dental Pulp Diseases; Embryo, Mammalian; Female; Fetus; Gestational Age; Maxilla; Mercaptopurine; Micrognathism; Nose Deformities, Acquired; Odontogenic Cysts; Pregnancy; Rats; Skull; Tooth Abnormalities; Tooth Germ

Topics: Abnormalities, Drug-Induced; Adenosine Triphosphate; Animals; Bone and Bones; Calcium; DNA; Female; Glycogen; Mercaptopurine; Muscle Proteins; Muscles; Phosphoric Monoester Hydrolases; Phosphorus; Pregnancy; Proteins; Rats; RNA

Topics: Abnormalities, Drug-Induced; Animals; Female; Mercaptopurine; Musculoskeletal Abnormalities; Pregnancy; Rats

Topics: Abnormalities, Drug-Induced; Animals; Blood Vessels; Brain; Diaphragm; Eye Abnormalities; Female; Fetus; Forelimb; Gestational Age; Hindlimb; Mercaptopurine; Methods; Microcephaly; Pregnancy; Rats; Skull; Tail; Urogenital Abnormalities

Topics: Abnormalities, Drug-Induced; Abnormalities, Severe Teratoid; Animals; Antineoplastic Agents; Cyclophosphamide; Face; Female; Gestational Age; Hydroxamic Acids; Hydroxyurea; Jaw Abnormalities; Limbic System; Mercaptopurine; Nitroso Compounds; Nose; Pregnancy; Rats

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

Topics: Abnormalities, Drug-Induced; Adenine; Animals; Chromatography; DNA; Female; Fetus; Glycine; Guanine; Mercaptopurine; Placenta; Pregnancy; Pregnancy, Animal; Rats; RNA; Spinal Dysraphism; Spine

Topics: Abnormalities, Drug-Induced; Animals; Azathioprine; Busulfan; Carbutamide; Congenital Abnormalities; Cyclophosphamide; Female; Gestational Age; Humans; Lipid Metabolism; Maternal Age; Measles; Mercaptopurine; Mice; Morphogenesis; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Radiation Injuries; Rats; Thalidomide; Tolbutamide

Topics: Abnormalities, Drug-Induced; Animals; Azathioprine; Extremities; Female; Mercaptopurine; Mice; Pregnancy; Rabbits; Rats

Topics: Abnormalities, Drug-Induced; Animals; Azaserine; Carcinoma, Ehrlich Tumor; DNA, Neoplasm; Female; Glucosyltransferases; Leukemia L1210; Mammary Neoplasms, Experimental; Mercaptopurine; Mice; Nucleosides; Oxidoreductases; Phosphotransferases; Pregnancy; Pregnancy, Animal; Sarcoma 180; Sarcoma, Experimental

Topics: Abnormalities, Drug-Induced; Animals; Central Nervous System; Eye Abnormalities; Female; Limb Deformities, Congenital; Mandible; Mercaptopurine; Mice; Pregnancy; Pregnancy, Animal; Rabbits; Rats

Topics: Abnormalities, Drug-Induced; Animals; Azathioprine; Cysteine; Embryo, Mammalian; Female; Glutathione; Mercaptopurine; Mice; Pregnancy; Rabbits; Rats; Species Specificity

Topics: Abnormalities, Drug-Induced; Animals; Azathioprine; Female; Mercaptopurine; Pregnancy; Rabbits

Topics: Abnormalities, Drug-Induced; Congenital Abnormalities; Dactinomycin; Fluorouracil; Humans; Mercaptopurine; Teratology

Topics: Abnormalities, Drug-Induced; Blood Transfusion; Dental Enamel; Female; Humans; Infant; Infant, Newborn; Leukemia; Leukemia, Myeloid; Mercaptopurine; Prednisone; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Tetracycline; Tooth Discoloration; Tooth, Deciduous; Toxicology

Topics: Abnormalities, Drug-Induced; Adenine; Female; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Pharmacology; Placenta; Pregnancy; Purines; Pyrazoles; Pyrimidines; Rats; Research; Teratogenesis; Thioguanine; Toxicology