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.

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.

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.

Diagnosis of early pregnancy by ultrasound in Macaca fascicularis.

Real-time ultrasonography was used to detect early pregnancy in 32 longtailed macaques (Macaca fascicularis). In 92% of the successful conceptions, a correct diagnosis was made. The earliest sign of pregnancy was an intrauterine ringlike structure (11 days). A "line swelling" (14 days) preceded definite fetal echoes (21 days), and fetal heart motion (30 days) proved fetal viability. Ultrasound is a rapid, noninvasive, and relatively cost-effective method of diagnosing and monitoring early pregnancy in M. fascicularis.

Anencephaly and twins: prenatal ultrasound and estriol.

A rare case of anencephalic twin pregnancy diagnosed prenatally with ultrasonography is reported. It is the only case found in the literature in which maternal 24-hour urinary estriol is documented in an anencephalic twin pregnancy. Ultrasound diagnosis and obstetric problems associated with such cases are discussed briefly.

Ultrasonic placental localization and bloody taps in midtrimester amniocentesis for prenatal genetic diagnosis.

In a prospective study, a small team of obstetricians concurrently performed midtrimester amniocentesis for prenatal genetic diagnosis on 32 patients after ultrasonic placental localization and on 50 patients without prior ultrasound. The use of ultrasound did not affect the red cell count in the fluid samples. Furthermore, the 2 patient groups had similar rates of grossly bloody taps. The average number of viable clones after culture was lower both after bloody taps and when ultrasound had been used, but in neither case was the difference significant. There were no postamniocentesis complications in the entire patient population. These results suggest that ultrasonic placental localization is not helpful in avoiding bloody taps, and that bloody taps may not necessarily be dangerous. Therefore, since the long-range hazards of in utero exposure to ultrasound may not yet be known, it would seem judicious to use preamniocentesis ultrasound selectively and on specific indication, rather than routinely.

Perturbations of the human menstrual cycle by oxymetholone.

The luteolytic activity of oxymetholone, and anabolic steroid, has been evaluated in 10 women. Administration early in the follicular phase of the cycle inhibited ovulation and prolonged the duration of the cycles in 2 of 3 subjects, but treatment beginning on Day 10 (3 subjects) did not prevent ovulation, although subsequent plasma progesterone concentrations were reduced. Treatment after ovulation (4 subjects) suppressed progesterone levels by 50 to 80 per cent and shortened cycle length by 6 to 8 days. Side effects were weight gain and bromosulfophthalein retention. The most likely mechanisms producing these perturbations are the inhibition of luteinizing hormone release early in the cycle and, later, inhibition of progesterone biosynthesis.

PIP: 10 ovulating women were treated with oxymetholone in 1 of 3 ways: 1) 50 mg twice daily every other day starting on the sixth day of the treatment cycle (early follicular phase), 2) 50 mg twice daily every other day starting in the late follicular phase (tenth day), or 3) 100 mg daily starting in early luteal phase. 2 women treated in early follicular phase had ovulation suppression and cycles prolonged 9 to 10 days, with progesterone suppressed by ovulated, and a third had a 71% suppression of progesterone. In the third group, cycle lengths were shortened due to a luteal phase shortening of 6 to 8 days, with progesterone values decreased 53 to 81%. Side effects noted were: weight gain (9 out of 10 patients) transient nausea, and increased bromsulphalein retention.