Diabetic pregnancy and perinatal morbidity.
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Biomedical subjects
Publications and source records attributed to M F Epstein.
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Lecithin is synthesized de novo in the lung by two biochemical pathways, choline incorporation and phosphatidylethanolamine methylation. These studies in the Macaca mulatta fetus and neonate have demonstrated the relative contributions of the two pathways and the timing in monkey gestation of increased pulmonary lecithin production.
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Bethamethasone was administered to pregnant rhesus monkeys of 134 to 150 days' gestation. At operative delivery, umbilical venous plasma cortisol concentrations were significantly lower in the treated group than in the control group, indicating that the agent crossed the placenta. In the treated group, accelerated differentiation was present in several fetal organs including lung, liver, kidney, and adrenal gland. Brain histologic changes suggestive of neuronal injury were found in some instances. There were no differences in the weights of these fetal organs except for liver. It was markedly increased in steroid-treated fetuses and this was accompanied by a fourfold rise in total hepatic glycogen content. These observations suggest that in the subhuman fetal primate, the differentiation of fetal organs in addition to lung is enhanced by short-term corticosteroid treatment while growth is not affected.
The amniotic fluid lecithin/sphingomyelin (L/S) ratio in normal rhesus monkey pregnancies exhibits a distribution through the latter half of gestation similar to that seen in human pregnancies. Changes in the synthesis and concentration of lecithin in the fetal lung, measured both in vitro and in vivo, are paralleled by changes in the amniotic fluid L/S ratio. Both the amniotic fluid L/S ratio and fetal lung lecithin concentration increase significantly (p less than 0.001) in the final 10 per cent of rhesus monkey gestation, and there is a significant correlation (p less than 0.001) between these two indices of fetal lung lecithin metabolism. Moreover, the onset of these late gestational changes is temporally related to increased activity of the major pathway of de novo lung lecithin synthesis and to the ability of the preterm rhesus newborn infants to remain free of respiratory symptoms after delivery by cesarean section. We conclude that the amniotic fluid L/S ratio is a valid indicator of fetal pulmonary phospholipid metabolism and, therefore, an accurate index of biochemical pulmonary maturity.
The two pathways for de novo lecithin (phosphatidylcholine) biosynthesis, choline incorporation (1) and phosphatidylethanolamine methylation (II), were examined simultaneously in lung and other tissues of Rhesus monkey fetuses. Cannulation of interplacental fetal vessels permitted studies on the intrauterine fetus without disruption of fetal-placental-maternal-amniotic fluid anatomic integrity. In contrast to observations with indirect techniques in the same species, direct measurement of the incorporation of isotopic precursors (3H-choline and 14C-ethanolamine) into lecithin indicated that pathway I predominates by 100-fold over PE methylation in pulmonary lecithin synthesis. Fetal liver, brain, and kidney also showed 10--70-gold greater choline incorporation that methylation activity. Measurement of lung phosphatidylcholine production via the two pathways in acidemic fetuses (umbilical venous pH less than 7.20) demonstrated marked inhibition of pathway I, but not II. It is concluded that the choline pathway is the major mechanism of lung lecithin synthesis in fetal primates and that this pathway is pH sensitive in vivo.
Sequential changes in maternal and fetal plasma and amniotic fluid concentrations of prolactin (PRL) and growth hormone (GH) were examined after these intravascular administration of thyrotropin releasing hormone (TRH) or L-dopa alone or combined directly to the near-term Rhesus fetus. The neonatal plasma responses to these same stimuli were also examined. Fetal and neonatal plasma PRL levels increased immediately after TRH injection and remained elevated from baseline levels (102-800%) throughout the 45 min sampling period. Maternal plasma PRL levels also increased markedly. Although amniotic fluid concentrations were more variable, the trend was an increase. After L-dopa injection, fetal and neonatal plasma PRL values declined 26-62% from baseline levels. Maternal plasma PRL concentrations also declined 30-50%, but amniotic fluid PRL concentrations progressively increased. When L-dopa and TRH were administered together, fetal plasma PRL levels declined 14-40% from initial levels, but maternal plasma PRL levels did not change in a consistent manner, and amniotic fluid PRL levels remained stable. There was no change from baseline fetal or neonatal plasma GH concentrations in these experiments. The plasma PRL responses of the primate conceptus to these stimuli are consistent with those found in the adult; the unresponsiveness of plasma GH is not. The direction and magnitude of changes in both maternal plasma and amniotic fluid PRL concentrations provide indirect evidence of placental transfer of TRH and L-dopa in some experiments, and require a biophysical explanation not apparent in others.
Fetal lung lecithin metabolism was examined in rhesus monkey gestations complicated by glucose intolerance secondary to maternal streptozotocin (STZ) administration. Fetuses of STZ-treated mothers were delivered at 85% to 89% of term and were compared to two control groups of fetuses from normal pregnancies--one group age-matched to the STZ pregnancies, and the other composed of fetuses delivered in the final 10% of gestation. In the glucose-intolerant pregnancies, two measures of fetal lung lecithin biosynthesis--the amniotic fluid lecithin-to-sphingomyelin (L/S) ratio and the rate of 14C-choline incorporation into lecithin in fetal lung slices--were significantly greater than in age-matched normal gestations and were similar to results in late-gestation controls. However, lung lecithin concentrations in the glucose-intolerant group were comparable to the age-matched controls, and both were significantly less than in the late-gestation controls. Since the gestational age, mode of delivery, and fetal acid-base status were the same in the age-matched groups, we conclude that these changes in fetal lung lecithin metabolism are due to the effects of maternal glucose intolerance.
Methods for percutaneous transabdominal amniocentesis and umbilical artery cannulation as modified and applied to the perinatal study of the rhesus monkey were described. These technics proved to be reliable, reproducible, and safe when used with care and attention to sterile technic.
Chronic intravascular catheterization in maternal, fetal, and neonatal sheep was utilized to assess basal plasma renin activity (PRA) and changes in PRA in response to furosemide. Maternal PRA increased from base-line levels during the last trimester of pregnancy and remained elevated for 12 wk postpartum. Fetal basal levels of PRA were variable but usually greater than maternal levels. Intravenous administration of furosemide to pregnant ewes resulted in a prompt and significant increase in maternal PRA with inconsistent changes in fetal PRA. Fetal and neonatal animals with low basal levels showed a significant increase in PRA; maternal PRA did not change. Animals with higher basal levels did not respond to the stimulus, perhaps reflecting a maximum renin secretory rate. These data are consistent with the conclusions that fetal renin originated predominantly from the fetal kidney, that fetal PRA receives no significant contribution from the maternal circulation, and that renin does not cross the ovine placenta.
Near-term fetal and neonatal parathyroid gland function has been studied in the Rhesus monkey. Fetal serum ionized calcium (Ca++) levels are significantly greater than simultaneously obtained maternal levels. Fetal serum parathyroid hormone (PTH) was undetectable both in the basal state and in association with EDTA-induced fetal hypocalcemia. Induced maternal hypocalcemia was associated with increased maternal serum PTH levels and no change in fetal basal serum Ca++ or PTH levels. Only a minimal decrease in simian neonatal serum Ca++ occurred over the first 48 h of life. Normal adult levels of serum PTH were present as early as 6 h of neonatal life. Induced hypocalcemia at 12 h of age resulted in a significant increase in serum PTH levels.
The two pathways of de novo lecithin synthesis, choline incorporation (I) and phosphatidylethanolamine methylation (II), were examined in lung slices from rhesus monkey fetuses throughout the last half of gestation. Incorporation rates of pathway-specific radioactive precursors were used as a measure of lecithin production. At all stages of development studied, pathway I incorporated 10-50 times more precursor ([14C]choline) into lecithin than did pathway II ([14C]methionine or [14C]ethanolamine). In addition, although methylation activity did not change significantly during gestation, choline incorporation showed three distinct phases: (1) a stable, relatively low rate in early gestation, (2) an abrupt, twofold increase at approximately 90 percent of term, and (3) a return to lower activity levels in late gestation. This correlates with reports that lung lecithin concentration in fetal primates increases significantly in the last 10 percent of gestation. The lecithin to spingomyelin (L/S) ratios measured in amniotic fluid samples obtained at abdominal delivery were compared with pathway activities in lung slices from the same fetuses. Significant correlation was found between the amniotic fluid L/S ratio and pathway I activity (r = 0.77, P less than 0.001); in contrast, pathway II activity showed no relationship to the amniotic fluid L/S ratio. Thus, the L/S ratio appears to be a reflection of lung lecithin synthesis through the choline pathway. The conclusion that the choline pathway is the primary route of de novo lecithin synthesis in the nonhuman fetal primate lung is supported by three lines of evidence, (1) the predominance of choline incorporation into lecithin, (2) the late gestational rise in conversion of choline to lecithin, and (3) the correlation between pathway I activity and both lung lecithin concentration and amniotic fluid L/S ratio.
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Brainstem auditory evoked potentials present a unique opportunity to assess the neuronal and auditory status of the newborn. To date, sample data have been few in number, thereby limiting their interpretive value. The present study was undertaken in an effort to accrue data generated from a large sample size. One hundred fifty-five normal neonates were tested within the first 36 hours of life. No subjects qualified for inclusion in the High Risk Register for Hearing Loss established by the American Academy of Pediatrics. Each ear was tested independently, using click stimuli at a rate of 30.1 per second at 65 dB HTL. Test runs were replicated for purposes of reliability. A run consisted of 2,000 sweeps of data, each being 10 ms in length. Identification of wave forms were assessed by two or more observers. Total agreement was required from all observers for inclusion of wave peaks for analysis. Latencies of onset of stimulus to peak were obtained. Descriptive as well as inferential statistics were computed. Results provide standardized data for comparison.