Effect of immunization on the development of latent ganglionic infection in mice challenged intravaginally with herpes simplex virus types 1 and 2.

Immunization of BALB/c mice with virulent and avirulent strains of HSV-1 resulted in high levels of neutralizing antibody and protected against both the lethal effect of the virus and the development of a latent ganglionic infection when animals were challenged by the intravaginal route. In animals immunized with avirulent strain of HSV-2 and challenged with a high virulent strain of HSV-2, substantial protection against death was observed despite low levels of neutralizing antibody. Nineteen per cent of the survivors, however, developed a latent ganglionic infection. Relatively little protection was observed in mice immunized with HSV-1 and challenged with HSV-2.     

One-year follow-up of infants exposed to ultrasound in utero

Neonatal and infant follow-up data from the Amniocentesis Registry of the National Institute of Child Health and Human Development were analyzed for possible effects of diagnostic ultrasound exposure in the second trimester of pregnancy. A total of 297 infants of mothers receiving both amniocentesis and diagnostic ultrasound were compared with a similar group of 661 infants of mothers who had amniocentesis but not ultrasound and with 949 infants exposed to neither amniocentesis nor ultrasound. Results of newborn and 1 year examinations were similar for the amniocentesis with ultrasound group when compared to the other two groups. However, in view of the small sample size and other limitations of these data, larger and more detailed studies are needed to adequately assess possible effects of ultrasound in pregnancy.     

Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep.

Propranolol was infused intravenously for 60 minutes to five ewes (4 mug per kilogram per minute) or five fetal sheep (10 mug per kilogram per minute). The umbilical blood flow was significantly decreased by 18 per cent from control at 60 minutes with either maternal or fetal propranolol infusion. Uterine blood flow and maternal and fetal mean arterial pressure did not significantly change. Maternal and fetal heart rates decreased 18 and 9 per cent from control, respectively, during maternal propranolol infusion. With propranolol to the fetus, fetal heart rate decreased 15 per cent and maternal heart rate did not change. During all infusion, maternal and fetal arterial pH, PCO2 and PO2 remained within normal physiologic limits.     

Carbonic anhydrase isoenzymes in normal human endometrium and erythrocytes

The total carbonic anhydrase activity of human endometrium doubled during the secretory phase of the menstrual cycle. Erythrocytes contained two isoenzymes that were also found in both proliferative and secretory phase endometrium, although these carbonic anhydrases were unaffected by hormonal changes that accompanied the normal menstrual cycle. In contrast, secretory phase endometrium contained a uterine-specific isoenzyme that was present only during the luteal phase of the menstrual cycle.     

The design of clinical trials in the therapy of ovarian carcinoma

Ovarian carcinoma continues to be a major cause of death in women in spite of the effective use of operation, radiotherapy, and chemotherapy in some patients. Improved survival will depend upon proper definition of prognostic factors, adequate and standardized staging, and upon prospective randomized clinical trials to define optimal existing therapy. With optimal existing therapy as a base line, newer therapeutic and combined modality approaches may be compared to optimal existing therapy in a systematic way. Results of such trials should improve survival of patients with ovarian carcinoma.     

Dynamics of adenosine-3', 5'- monophosphate transfer among mother, fetus, and amniotic fluid in the rhesus monkey.

Cyclic AMP exchange among the mother, amniotic fluid, and fetus was studied in normal rhesus monkeys at term pregnancy. Following a pulse intravenous administration of 3H-cyclic AMP into the mother, a small fraction of the dose appeared in less than 1 minute in fetal blood. It appeared in the amniotic fluid after 5 minutes and reached maximum level in 20 minutes. The accumulation of 3H-cyclic AMP in the amniotic fluid in 1 hour was 0.03 per cent of the injected dose. The amount and time course of 3H-cyclic AMP accumulation in the fluid were not altered by tying the umbilical vessels. The transfer of 3H-cyclic AMP injected in utero into the fetal femoral artery resembled that in the mother; in 1 hour the amniotic fluid contained 0.22 per cent of the injected dose. When injected directly into the amniotic sac, more than 65 per cent of the injected dose remained unchanged after 1 hour, with minimal transfer into the maternal and fetal compartments. This study showed rapid bidirectional exchange of cyclic AMP between the mother and the fetus. Both of these compartments can contribute cyclic AMP to the amniotic fluid, independently or in concert. It remained fairly stable in the fluid and was not readily metabolized or transported out.     

Glucocorticoids and the rhesus fetal lung.

The effects of glucocorticoids on primate fetal lung function have not been clearly delineated. In this prospective study of preterm rhesus fetuses exposed in utero to betamethasone for 72 hours, the most significant alteration was a striking increase in maximum lung volumes. Functionally less significant increases in residual lung volumes were also noted. The lungs of the treated fetuses did not exhibit lower extract surface tensions or increased phospholipid concentrations. These findings suggest that the major effect of betamethasone is on lung connective tissue elements, with minimal effects on alveolar surfactant. Additional evidence of the multisystemic effects of glucocorticoids was obtained in that significant differences in fetal, adrenal, hepatic, and placental weights also were observed.     

Intrauterine growth of chronically instrumented rhesus monkey fetuses

The effect of surgical and experimental manipulations on intrauterine growth of the fetus was investigated in 61 rhesus monkey fetuses in which chronic preparations were attempted. The surgical procedure consisted of hysterotomy and insertion of vascular catheters and included unilateral ligation of the fetal carotid artery. The mother was kept in a restraining chair after the operation for the duration of the preparation (0 to 39 days). Thirty-four fetuses who died within 48 hours after operation served as the control group for the growth parameters. The remaining fetuses that survived 7 days or more after the operation were included in the experimental group. Body weight, crown-rump length, crown-heel length, and foot length of the fetus and placental weight were measured at the termination of the preparation. There were significant linear correlations between all parameters and gestational age. Comparison between the control and experimental groups revealed that none of the parameters from the experimental group differed significantly from those of the control group. No relationships were found between the duration of the preparation and any of the parameters. Total brain weights from 19 fetuses exhibited a significant increase with gestational age and these values were within the normal range reported previously. There were no significant differences in weight between right and left cerebral hemispheres. No evidence of unequal blood flow to the cerebral hemispheres was found with the radioactive microsphere technique. The data suggest that the surgery performed on both the mother and the fetus and prolonged maternal restraint did not alter intrauterine fetal development.     

Effect of nicotine upon uterine blood flow in the pregnant rhesus monkey

Acute effects of nicotine upon the uterine blood flow, blood pressure, maternal and fetal acid-base state, and oxygenation were determined in eight pregnant rhesus monkeys near term. Nicotine was infused intravenously to the mother in a dose of 100 microgram/kg per body weight/minute over 20 minutes. The flow rate was measured with the use of the electromagnetic flowmeter. Significant decrease in the uterine arterial blood flow rate, as much as 38% of the control value, was observed during the first 15 minutes of the infusion while aortic pressure increased by 14%. Acidosis and hypoxia resulted in the fetus. Considered together with our previously reported data, the present investigation appears to indicate that the adverse effects of nicotine to the fetus are due to the combined effects of the reduced uterine blood flow and the transmitted nicotine to the fetus.     

Effects of a beta-adrenergic agent (metaproterenol) on uteroplacental circulation. An angiographic study in the pregnant rhesus monkey

Placental radioangiography was performed in 13 lightly anesthetized pregnant rhesus monkeys under standardized conditions. Amniotic, aortic, and central venous pressures as well as the maternal electrocardiogram (ECG) were continuously monitored. In six experiments intravenous infusion of a small amount of metaproterenol was shown to accelerate the angiographic appearance of intervillous spurts due to vasodilatation. This effect could be partially blocked by propranolol and thus would appear to be caused by stimulation of vascular beta-adrenergic receptors. Evidence is adduced that accelerated uteroplacental circulation in this experimental model means increased uteroplacental blood flow. In analogy, administration of small amounts of a beta-adrenergic agent in cases of impaired uteroplacental blood flow due to vasospasm in man might lead to vasodilatation and consequently might improve uteroplacental flow and fetal condition.     

Determination of disaturated lecithin in rhesus monkey amniotic fluid as an index of fetal lung maturity.

Although increased concentrations of total lecithin in amniotic fluid allow prenatal assessment of fetal lung maturation, it has become clear that routine use of the L/S index may lead to a substantial number of inaccurate predictions. Since disaturated lecithin (DL) is a more specific marker of pulmonary surfactant than total lecithin, we developed a convenient method for measuring this phospholipid in amniotic fluid, and then evaluated its level in pregnant rhesus monkeys of 120 to 163 days of gestation. The method involves osmic acid destruction of unsaturated lipids, chromatographic isolation of disaturated lecithin, and quantitation by phosphorus assay. It can be performed in approximately 5 hours on 4 ml. of amniotic fluid and yield 67 +/- 3 per cent average recovery of added 14C-dipalmitolyl lecithin. The results of analyzing 36 rhesus amniotic fluid specimens showed the disaturated lecithin and the disaturated lecithin/sphingomyelin ratio (DL/S) increase sharply after 150 days of gestation, consistent with the pattern of lung maturation in this species. We conclude that disaturated lecithin can be readily quantitated in primate amniotic fluid and that its concentration, the DL/S ratio, and percentage of disaturated lecithin are potentially useful indices of fetal lung maturity for the clinical laboratory.     

Late decelerations and brain tolerance of the fetal monkey to intrapartum asphyxia.

Eight monkey fetuses near term were subjected to regulated asphyxia during labor by mechanically constricting the maternal abdominal aorta and diminishing blood flow to the uterus. A magnitude of asphyxia was produced and maintained for an initial three hours that was close to but not sufficient to elicit late decelerations. The asphyxia was then augmented during a fourth hour to cause late decelerations of magnitudes of 5 to 15 per cent of the initial heart rate. After termination of the fourth hour of asphyxia, the fetuses were delivered by hysterotomy and provided intensive care. During the three to nine months of survival after birth, all animals were neurologically intact; on necropsy the brains were free of pathologic changes both grossly and microscopically. These results support the thesis that fetal heart rate monitoring during labor exhibits a sensitivity sufficient to diagnose asphyxia of the fetus of clinical significance before it reaches a magnitude that may cause permanent neurological injury. The results are particularly pertinent to those clinical circumstances where the decreases in intervillous space blood flow brought about by uterine contractions are accentuated due to low maternal blood pressure.     

Circadian hormonal interactions among the mother, fetus, and amniotic fluid

Circadian rhythms and hormonal interactions among the maternal, fetal, and amniotic fluid compartments were studied in long-term catheterized rhesus macaque monkeys between days 127 and 138 of gestation (term = 167 days). Blood samples were collected at 3-hour intervals for 48 hours and analyzed by radioimmunoassay for estrone, estradiol, cortisol, progesterone, dehydroepiandrosterone sulfate, and prolactin. Distinct circadian rhythms were present for cortisol and progesterone in the maternal circulation and for progesterone and dehydroepiandrosterone sulfate in the fetal circulation (p less than 0.05). Although maternal and fetal estrogen levels were higher in AM samples than in PM samples, a statistically significant circadian rhythm was not present (p greater than 0.10). Fetal levels of progesterone and dehydroepiandrosterone sulfate and maternal levels of progesterone were highest between 9:00 PM and 3:00 AM and lowest between 9:00 AM and 3:00 PM. Maternal levels of cortisol were highest between 6:00 AM and 9:00 AM and lowest between 6:00 PM and 12 midnight. The circadian patterns of maternal cortisol and progesterone were inversely related to each other (r = -0.68; p less than 0.01). Amniotic fluid cortisol levels were highest between 9:00 AM and 12 noon and lowest between 6:00 PM and 3:00 AM (p less than 0.10). With the possible exception of cortisol, amniotic fluid steroid hormones did not demonstrate distinct diurnal fluctuations, nor did they correlate with steroid changes in maternal or fetal blood. Because the rhesus placenta is permeable to glucocorticoids it is likely that transplacental passage of maternal cortisol influences the activity of the fetal pituitary and adrenal so that the circadian rhythm in the fetal axis is 180 degrees out of phase with that of the maternal axis. The circadian rhythms in fetal dehydroepiandrosterone sulfate and progesterone in late gestation parallel the biorhythm in uterine contraction frequency and amplitude, with peaks during periods of darkness between 9:00 PM and 3:00 AM.     

Antibody to type III group B Streptococcus in the rhesus monkey

Susceptibility to infection due to intra-amniotic type III group B streptococcal infection was studied in 27 rhesus monkeys. Sera from mothers and their offspring were tested to determine the concentration of antibody to the native type III group BStreptococcus antigen. Among 17 controls there was a statistically significant association between the concentration of maternal antibody prior to infection and both the neonatal survival rate and survival time (P < 0.05). Neonatal survival was decreased to ≤6 hours (P = 0.005) if the maternal antibody concentration was <0.5 μg/ml. Modified immune serum globulin was given intravenously to the mothers prior to intra-amniotic infection with (five animals) or without (five animals) neonatal modified immune serum globulin. Neither of the modified immune serum globulin groups demonstrated a significant reduction in the neonatal mortality rate; however, the addition of the modified immune serum globulin provided protection against rapid neonatal death among those animals born to mothers which had low or no detectable antibody. All maternal groups developed a significant increase in the concentration of antibody in postpartum sera. These results indicate that both naturally acquired and passive (modified immune serum globulin) antibodies to type III group BStreptococcus antigen are partially protective against intra-amniotic infection.     

Serum concentrations of beta-melanocyte-stimulating hormone in human pregnancy

β-Melanocyte-stimulating hormone (β-MSH) has been measured in pregnant women with the use of a sensitive tube radioimmunoassay technique which does not require prior extraction. This peptide rises progressivley throughout pregnancy with its highest concentration at term. Measurable quantities exceeding maternal levels were observed in both cord blood and amniotic fluid and elevated levels of β-MSH were found in lactating women. The role and possible chorionic origin of β-MSH remain to be determined, as well as the possible clinical use.     

Responses of the growth-retarded fetus to acute hypoxemia

Growth retardation in the human fetus associated with maternal cardiovascular disease is frequently accompanied by birth asphyxia and perinatal mortality. We have investigated the cardiovascular responses to acute hypoxemia in the fetal lamb with growth retardation secondary to embolization of the uteroplacental vascular bed. In the basal period, fetal arterial P_O2 and umbilical perfusion were significantly lower, and perfusion of the adrenal glands, brain, and heart was significantly higher, in embolized than in control fetal lambs. During imposed acute hypoxemia there was preferential perfusion of vital organs, the adrenal glands, brain, and heart in control and embolized fetuses. This preferential perfusion to the vital organs during hypoxemia was significantly more pronounced in embolized animals. Because of the increased compensation during acute hypoxemia, as reflected by the increased preferential perfusion of vital organs, the growth-retarded fetuses would probably decompensate sooner if the hypoxemia was prolonged.     

Vasoactive substances in the circulation of the pregnant dog during acute fetal ischemia

Uterine venous blood from anesthetized dogs in late pregnancy was assayed for vasoactive substances during acute uterine ischemia by means of the blood-bathed bioassay technique. Short periods of reduction of uterine perfusion pressure to 60 mm. Hg or less caused the liberation into the maternal circulation of two vasoactive materials. One of these materials resembled angiotensin II; the other was an unidentified relaxatory factor. These substances were not released during reduction of uterine perfusion pressure after ligation of all umbilical cords. The results are compatible with a role for vasoactive materials of fetal origin in maternal circulatory disorders associated with fetal insufficiency.