Fetal toxicity of zidovudine (azidothymidine) in Macaca nemestrina: preliminary observations.

The objective of this study was to determine the dam, fetal, and infant toxicity of zidovudine (AZT) administered to pigtailed macaques during pregnancy. Pregnant macaques were administered AZT (1.5 mg/kg/dose every 4 h) or water via gastric catheter throughout pregnancy. AZT concentration and hematological changes were monitored in the dam, and fetal growth was monitored via ultrasound. Infant hematocrit was assessed at birth, and the neurological, perceptual, and motor development of the offspring were assessed for 9 to 10 months. Twelve pregnancies were brought to term. Mean plasma concentrations of AZT were comparable to those in human studies. Hemoglobin dropped significantly in pregnant dams and remained low, whereas platelets increased during treatment but returned to normal before the end of the study. There were no significant differences in any ultrasound measure of fetal growth, and AZT-exposed infants exhibited little behavioral delay or impairment. We predict no significant toxic effects of prenatal AZT exposure at this dosage in humans.

Weaning, body weight, and postpartum amenorrhea duration in pigtailed macaques (Macaca nemestrina).

Early permanent infant separation or weaning decreases the time interval between pregnancies and interbirth intervals for many female primates. At least part of the interpregnancy interval consists of postpartum amenorrhea, a period of non-menstruation lasting from the time of birth until the female begins to ovulate. This study investigated the effects of weaning age and dam's body weight on the duration of the interval between pregnancies, the duration of postpartum amenorrhea, and the number of cycles to conception in a year-round breeder. Female pigtailed macaques (Macaca nemestrina) have an observable perineal swelling that fluctuates throughout the menstrual cycle and provides a means of detecting ovulation. The perineal swelling records of socially housed pigtailed macaques were studied from July 1996 to September 1998. Postpartum amenorrhea data were obtained on 44 females who gave birth to normal, viable infants. As weaning age increased and dam's weight decreased, postpartum amenorrhea, and consequently the interval between pregnancies, increased in duration. The interpregnancy interval consisted almost entirely of the postpartum amenorrhea phase. Our finding that a higher dam's body weight decreased the length of postpartum amenorrhea duration lends support to the hypothesis that a minimum body weight is necessary for menstrual cycles to occur. Most females became pregnant on their first ovulation regardless of weaning age and whether or not they were carrying an infant. As the weaning age of the infant and the dam's weight increased, ovulation went from occurring after separation to occurring before separation.

Assessment of fetal and placental blood flow in primates using contrast enhanced ultrasonography.

Ultrasonographic contrast agents that stay within the vascular space and do not cross the placenta may permit differentiation between the maternal and fetal portions of the placenta and may be clinically useful for diagnosis of placental abnormalities. This study was performed to assess the effects of Levovist (Schering AG, Berlin) on the placental circulation and to determine whether hemodynamic effects on the fetus occur. Ten studies were performed in five pregnant macaques (median weight, 9.15 kg; range, 6.15 to 11 kg; median gestational age, 121 days; range, 34 days to term) under anesthesia. Gray scale, color, and duplex Doppler sonographic scans of the fetus and placenta were acquired using a 5 MHz curved array transducer. Fetal heart rate, resistive index, and systolic-diastolic ratios were measured in the fetal middle cerebral artery, aorta, umbilical artery, and uterine artery before and after administration of contrast agent. The following dose regimen was tested: 5 ml of physiologic saline solution followed by 0.1 ml/kg of 300 mg/ml Levovist (diagnostic dose), 0.5 ml/kg of 400 mg/ml Levovist (maximum dose), and 5 ml physiologic saline solution. The order of diagnostic dose and maximal dose was randomized among animals. Color enhancement of the basal portions of the placenta was documented after administration of contrast agent. Heart rate and middle cerebral artery systolic-diastolic ratio did not change between baseline and injections. A 7% decrease of the resistive index from baseline to maximum dose was measured in the uterine artery (not significant). A 7.7% decrease in the systolic-diastolic ratio from baseline to maximum dose was recorded in the umbilical artery. However, an identical change was measured after saline solution was injected. The resistive index in the aorta increased by 2.6% from baseline to maximum dose, a change that was not significant (P > 0.5). Ultrasonographic contrast enhancement of the maternal circulation in placenta is demonstrated to be without significant effects on the fetal circulation as measured in this limited population.

Pigtailed macaques (Macaca nemestrina) with trisomy X manifest physical and mental retardation.

Three pigtailed macaques (Macaca nemestrina) from a nursery population were predicted to be genetically abnormal based on observations of anatomical and behavioral development. All three exhibited delays in skeletal, visual, intellectual, and social development, suggesting a chromosomal syndrome. Karyotypes showed that two animals were XXX females, and the third was a mosaic XX/XXX female.

Fetal, infant, and maternal toxicity of zidovudine (azidothymidine) administered throughout pregnancy in Macaca nemestrina.

The toxicity of azidothymidine (AZT) was studied in monkey dams and fetuses that were exposed to the drug over the entire gestational period. Fourteen virus-free female macaques (Macaca nemestrina) were randomly assigned to AZT or control groups. AZT animals received the drug through a gastric catheter at a dose of 1.5 mg/kg every 4 hours, which produced plasma concentrations similar to those in humans taking 500 to 600 mg/day of AZT. Control animals received water placebo, also through gastric catheter. Some animals participated in both groups. All females were mated with the same male; 41 matings produced 20 pregnancies, of which 16 were carried to term (9 in AZT females; 7 in control females). The AZT animals developed an asymptomatic macrocytic anemia, but hematologic parameters returned to normal when AZT was discontinued. Total leukocyte count decreased during pregnancy and was further affected by AZT administration. AZT-exposed infants were mildly anemic at birth. AZT caused deficits in growth, rooting and snouting reflexes, and the ability to fixate and follow near stimuli visually, but the deficits disappeared over time. These data indicate that early exposure to AZT in utero should have no irreversible adverse effects on the fetus.

Mosaic variegated trisomy (42,XY/43,XY, + variable) in a male pigtail macaque monkey.

We identified an infant male pigtail macaque monkey with a bizarre karyotype which, to the best of our knowledge, has never before been reported in any species. Examination of 107 nuclei from cultured lymphocytes revealed 81 (75.7%) to be trisomic, but with the supernumerary chromosome varying from cell to cell, trisomy 16 being the most common. A small percentage (11.2%) of the nuclei had a normal 42,XY karyotype, and the balance, with the exception of one apparent monosomic (possibly a technical artifact), had multiple chromosome abnormalities. Examination of cultured skin fibroblasts revealed a similar karyotype. We called this karyotype a mosaic variegated trisomy. At birth, the animal had a cleft lip and palate and situs inversus of the heart. He subsequently showed significant developmental delay and apparent mental retardation. There were no clinical symptoms of hematological malignancy, which often have associated acquired chromosome abnormalities such as those described here. The animal survived for 2 yr and 8 mo under intensive care.

Reproduction and sera embryotoxicity after immunization of monkeys with the laminin peptides YIGSR, RGD, and IKVAV.

Monkeys with excellent reproductive histories were immunized with the laminin peptides YIGSR, RGD, IKVAV, and YD, a control sequence with no known biological function. Sera from the YIGSR-immunized monkey became toxic, causing neural tube defects in whole rat embryo cultures, and this monkey experienced fetal loss after immunization. Sera from the RGD-immunized monkey also became embryotoxic in culture after immunization, but this monkey appeared to become infertile as she failed to initiate a pregnancy for at least 2 years after immunization. In contrast, embryos cultured on sera from the IKVAV- or YD-immunized monkeys were predominantly normal and both monkeys completed successful pregnancies. Antibody levels to the respective peptides or to laminin were not predictive of embryotoxicity, but antibody binding to homogenized yolk sacs as well as to yolk sacs of cultured embryos was associated with sera embryotoxicity and reproductive outcomes in vivo. These observations suggested that the laminin sequences YIGSR and RGD may play a role in immune-mediated reproductive failure by reacting directly with embryonic tissue and could provide a basis for identifying individuals at risk for both spontaneous abortion and infertility.