Fetal development in mice exposed to isoflurane.

The developmental toxicity of trace (0.006%), subanesthetic (0.06%), and light anesthetic (0.6%) exposure to isoflurane was examined in Swiss/Webster mice. No adverse effects were demonstrated following exposure of dams to 0.006% (n = 26) and 0.06% (n = 27) isoflurane for 4 hr daily on days 6-15 of pregnancy. Exposure to 0.6% isoflurane (n = 23) for the same period resulted in significantly decreased fetal weight, decreased skeletal ossification, minor hydronephrosis, and increased renal pelvic cavitation. The incidence of cleft palate also was significantly increased, abnormalities occurring in 12.1% of fetuses and affecting 11 of 23 litters. This incidence was considerably higher than that of the combined treatment and colony control groups (0.75%) and those that we have found in previous experiments with this mouse strain following exposure to halothane (1.2%) or enflurane (1.9%).

Reproduction and fetal development in rats exposed to nitrous oxide.

The effects of 24 hours of nitrous oxide exposure on reproductive indices and fetal development were examined in Sprague-Dawley rats. Four different experiments employing four concentrations of nitrous oxide--0.75%, 7.5%, 25% and 75%--established that the threshold of toxicity was greater than 25%. At 75% nitrous oxide there was a significant increase in early and late resorptions, and a consistent teratogenic effect (e.g., runts, ocular malformations, limb deformities). Neither the stress of shipping dams while pregnant nor the withholding of food during nitrous oxide exposure resulted in additional adverse effects. Exposure to 25% nitrous oxide was associated with increased deoxyuridine suppression values; however, adverse reproductive effects were not seen at this nitrous oxide concentration. The results of this and other studies which have examined the reproductive and teratogenic effects of nitrous oxide do not contraindicate its use in operating rooms nor, when necessary, as an anesthetic for pregnant surgical patients.

Amniotic fluid phospholipid profile in multiple pregnancy and the effect of zygosity.

Because respiratory distress syndrome (RDS) may occur in one twin but not the other it may be misleading to assess fetal lung maturity using amniotic fluid from only one sac. We compared the amniotic fluid lecithin/sphingomyelin (L/S), phosphatidyl glycerol/sphingomyelin (PG/S) and phosphatidyl inositol/sphingomyelin (PI/S) ratios between co-twins and co-triplets in 32 sets of twins and three set of triplets. In the twin pregnancies we found a weak correlation for L/S ratio but a much improved one for PG/S and PI/S. The concordance between sacs for all three ratios was better in monozygotic than in dizygotic twins. The efficacy of amniotic fluid PG in the determination of fetal lung maturity was demonstrated and the discrepancies between the sacs was much less for PG than for the L/S ratios. Employing the L/S ratio combined with the presence or absence of PG should reduce false results to a minimum.

Amniotic fluid phosphatidylglycerol: an early indicator of fetal lung maturity.

In a study of 766 amniotic fluids, collected from pregnancies between 26 weeks and term, phosphatidylglycerol (PG) was identified in a greater proportion than was a mature lecithin/sphingomyelin (L/S) ratio at all gestational ages between 28 and 38 weeks regardless of the underlying pregnancy complication. The early appearance of PG was particularly striking in amniotic fluids obtained after preterm rupture of membranes. Since PG has been previously shown to be a useful indicator of the risk of neonatal respiratory distress syndrome, its appearance before a mature L/S ratio suggests that its detection offers a considerable advantage in the management of high-risk obstetric problems in which the earliest possible indication that the fetal lungs are mature is required.

Amniotic fluid phosphatidylglycerol and the lecithin/sphingomyelin ratio in the assessment of fetal lung maturity.

Based on the analysis of 561 amniotic fluid samples obtained within 72 h of delivery, including 288 samples collected from the vagina, the detection of phosphatidylglycerol (PG) in the fluid together with the determination of the lecithin/sphingomyelin (L/S) ratio gave an accurate prediction of the risk of the newborn infant developing respiratory distress syndrome (RDS). In the presence of PG, regardless of the L/S ratio, only 0.6% of the babies developed RDS, while absent PG was associated with an 82.8% incidence of RDS. The predictive ability was improved by knowing the L/S ratio since in the presence of both PG and a mature L/S ratio (greater than 2.0), no baby developed RDS whereas 3.4% of them did when the ratio was immature despite the presence of PG. The test appears to be a useful determinant of the risk of RDS in babies born to diabetic mothers and it seems particularly effective in assessing amniotic fluid collected vaginally. It is recommended that laboratories dealing with amniotic fluid from high-risk pregnancies should detect PG as well as measuring the L/S ratio.

Reproduction and fetal development in mice chronically exposed to nitrous oxide.

The effects of exposure to nitrous oxide on reproductive indices, fetal development, and male fertility were examined in Swiss/ICR mice. In experiment I, female mice were exposed for 4 hours per day on days 6-15 of pregnancy, to 0.5% (5,000 ppm), 5.0% (50,000 ppm), or 50% (500,000 ppm) nitrous oxide. Control mice were untreated, exposed to compressed air, or treated with retinoic acid on day 8 of gestation. In experiment II, male mice were treated, as above, for 9 weeks and then mated nightly for 7 nights to untreated, virgin females. In experiment I, 1,761 fetuses from 154 dams were examined and found to be without evidence of adverse nitrous oxide treatment effects. In experiment II there were no differences among the groups in the ability of males to impregnate females or in litter size, fetal wastage, or fetal size. When we compare nitrous oxide with other inhalation anesthetics we have studied employing a similar protocol, we find the order of reproductive toxicity to be: halothane greater than enflurane greater than methoxyflurane greater than nitrous oxide. None of the agents were toxic, however, at the trace concentrations usually found in operating rooms.

Reproduction and fetal development in mice chronically exposed to enflurane.

Reproductive indices and developmental toxicity were evaluated in Swiss/ICR mice chronically exposed to a subanesthetic (0.01 or 0.1 per cent) or an anesthetic (0.5/1.0 per cent) concentration of enflurane. Pregnant mice (443) and fetuses (4743) were examined. In one experiment, groups of females were exposed to 0.01, 0.1, or 0.5/1.0 per cent enflurane for 4 hours per day, 7 days per week for 3 weeks; they were then mated with unexposed males. Exposure of females was continued daily throughout pregnancy. No adverse effects on fertility were observed at any dosage. At the highest dosage, 1.0 per cent, minor developmental variations occurred (i.e., lumbar ribs and increased renal pelvic cavitation). In a second experiment, groups of mice were exposed to 0.01, 0.1 or 1.0 per cent enflurance only on days 6 through 15 of pregnancy for 4 hours per day, after having been mated with untreated males. Abnormalities (i.e., increased incidence of cleft palate, minor skeletal and visceral anomalies, and developmental variants) were again seen only at the highest dosage. In a third experiment, male mice were exposed to 0.01, 0.1 or 0.5/1.0 per cent enflurane for 11 weeks for 4 hours per day, 5 days per week, prior to mating with unexposed females; results of this experiment were negative. In general, enflurane treatments did not adversely affect reproductive indices. Effects on fetal development were minimal, being somewhat greater than those reported in previous experiments with methoxyflurane but less than those seen with halothane. The smallest exposure at which effects were seen was approximately 100 times greater than the level of human occupational exposure in unscavenged operating rooms.

Amniotic fluid phospholipid profile determined by two-dimensional thin-layer chromatography as index of fetal lung maturation.

A phospholipid profile, the main features of which were the lecithin/sphingomyelin (L/S) ratio and the presence or absence of phosphatidylglycerol (PG), was determined in amniotic fluid from 188 patients. There was a mature profile (L/S ratio of at least 2 . 0 and detectable PG) in 145 patients, including seven insulin-dependent diabetics, and noe of their babies developed respiratory distress syndrome (RDS). The L/S ratio was less than 2 . 0 and PG absent in 12 patients, nine of whose babies developed RDS, whereas only three small babies (delivered between 28 and 35 weeks because of fulminant pre-eclampsia or severe abruptio placentae) out of 31 developed RDS when the L/S ratio was less than 2 . 0 but PG was present. When amniotic fluid was collected from the vagina only one out of 69 babies developed RDS when PG was present (regardless of the L/S ratio), while all of seven babies developed RDS when PG was absent. It is concluded that the amniotic fluid phospholipid profile, particularly the presence or absence of PG, gives an accurate assessment of fetal lung maturation. The profile may prove a useful adjunct to the management of high-risk pregnancies, especially after premature membrane rupture and perhaps also when the mother is diabetic.

Fetal morphology in mice exposed to halothane.

The teratogenic potential of subanesthetic and anesthetic exposure to halothane was studied in Swiss/ICR mice. Two treatment regimens were employed: daily exposure of males and females for nine weeks prior to conception and on days 1 through 17 of pregnancy; and exposure of females only on days 6 through 15 of pregnancy. Mice were exposed to subanesthetic concentrations of halothane for 0.025, 0.1, 0.4, and 1.2 MAC hours/day; anesthetic exposure was 4.0 MAC hours/day. Fetal morphologic development was normal at the two lowest exposures. Exposures of 0.4 MAC hours/day and more were associated with decreased fetal ossification. At the 1.2 MAC hour/day exposure, renal pelvic masturation was retarded and the incidence of skeletal variants was increased. The incidences of major malformations and minor anomalies were not increased following exposure to subanesthetic concentrations of halothane. Anesthetic exposure to 4.0 MAC hours/day was lethal to both dams and embryos, and resulted in major developmental malformations in surviving fetuses. These effects were probably due to altered maternal physiologic status. It is concluded that exposure of mice to subanesthetic concentrations of halothane does not result in important morphologic abnormalities in their offspring.