The solubility and site preference of Fe3+ in Li7-3x Fe x La3Zr2O12 garnets.

A series of Fe3+-bearing Li7La3Zr2O12 (LLZO) garnets was synthesized using solid-state synthesis methods. The synthetic products were characterized compositionally using electron microprobe analysis and inductively coupled plasma optical emission spectroscopy (ICP-OES) and structurally using X-ray powder diffraction and 57Fe Mössbauer spectroscopy. A maximum of about 0.25 Fe3+ pfu could be incorporated in Li7-3x Fe x La3Zr2O12 garnet solid solutions. At Fe3+ concentrations lower than about 0.16 pfu, both tetragonal and cubic garnets were obtained in the synthesis experiments. X-ray powder diffraction analysis showed only a garnet phase for syntheses with starting materials having intended Fe3+ contents lower than 0.52 Fe3+ pfu. Back-scattered electron images made with an electron microprobe also showed no phase other than garnet for these compositions. The lattice parameter, a0, for all solid-solution garnets is similar with a value of a0≈12.98 Å regardless of the amount of Fe3+. 57Fe Mössbauer spectroscopic measurements indicate the presence of poorly- or nano-crystalline FeLaO3 in syntheses with Fe3+ contents greater than 0.16 Fe3+ pfu. The composition of different phase pure Li7-3x Fe x La3Zr2O12 garnets, as determined by electron microprobe (Fe, La, Zr) and ICP-OES (Li) measurements, give Li6.89Fe0.03La3.05Zr2.01O12, Li6.66Fe0.06La3.06Zr2.01O12, Li6.54Fe0.12La3.01Zr1.98O12, and Li6.19Fe0.19La3.02Zr2.04O12. The 57Fe Mössbauer spectrum of cubic Li6.54Fe0.12La3.01Zr1.98O12 garnet indicates that most Fe3+ occurs at the special crystallographic 24d position, which is the standard tetrahedrally coordinated site in garnet. Fe3+ in smaller amounts occurs at a general 96h site, which is only present for certain Li-oxide garnets, and in Li6.54Fe0.12La3.01Zr1.98O12 this Fe3+ has a distorted 4-fold coordination.

Diurnal rhythms of fetal and maternal heart rate in the baboon.

To investigate the organization of diurnal rhythmicity during gestation, the relationship between daily cycles of maternal and fetal heart rate were measured in long-term studies of healthy chronically instrumented pregnant baboons. In each of six pregnancies, hourly mean values over a 168 h time series were obtained during a 7 to 10 day interval between 135 and 160 days of gestation. Data were modeled by a least squares fit to a cosine function with a period of 24 h. Hourly mean heart rate in the fetus ranged from 161 to 172 bpm (167.9+/-0.6 bpm), and the mother from 105 to 125 bpm (107.9+/-1.4 bpm). The amplitude of the daily fluctuations were 15 to 25 bpm for the fetuses and 25 to 60 bpm for the mothers. The relation between time series data and model estimates were significant (P < 0.001) in all cases with aggregate r2 = 0.747 for fetuses and 0.737 for the mothers. On average the time of day of the peak in fetal heart rate (15:05+/-0.3 h) was about 45 min after the maternal peak (14:21+/-0.4 h). This phase delay was significant (t = 2.63, P < 0.05). There was significant (P < 0.01) diurnal periodicity for each of six parameters used to assess different aspects of fetal heart rate variability with peak variability at night (23:00 to 2:00). Thus, during the latter third of pregnancy in both the maternal and fetal baboon 24 h periodicities of heart rate are present with peak rates in the midafternoon. The daily rhythms in fetal heart rate are linked with periodicities in maternal heart rate with a phase delay in the majority of cases. The synchrony of 24 h fluctuations in rate with parameters of rate variability is consistent with diurnal input into the fetal autonomic nervous system.

CCR5 genotype and resistance to vertical transmission of HIV-1.

A human gene has been identified that affects susceptibility to HIV-1 infection. The gene codes for CCR5, the coreceptor for macrophage-tropic strains of HIV-1. Individuals who are homozygous for a deleted, mutant form of the gene, delta32, display a high degree of natural resistance to sexual and parenteral transmission of HIV-1. To investigate whether delta32 plays a role in vertical transmission, we determined the CCR5 genotype of 552 children born to infected mothers in the United States and correlated the genotypes with HIV-1 infection status. Of these children, 13% were white, 30% Latino, and 56% African American, reflecting the ethnic makeup of infected women in the United States. The delta32 gene frequency varied among these groups, ranging from 0.08 in whites to 0.02 in both Latinos and African Americans. Approximately 27% of the children in each ethnic group were infected. Four children were identified as delta32 homozygotes, two uninfected whites (3.77%) and two uninfected Latinos (1.68%). None of the infected children displayed the delta32 homozygous genotype. Among Latinos and whites, the number of uninfected children who carried the homozygous delta32 mutation was significantly greater than that predicted by the Hardy-Weinberg equilibrium (p < .001 for Latinos, p = .044 for whites). This association was noted in Latino and white children whose mothers were either treated or untreated with zidovudine. These data document the occurrence of the homozygous delta32 genotype among children of HIV-1-infected mothers and suggest that this mutant genotype may confer protection from mother-to-child transmission of HIV-1. They also suggest that sexual, parenteral, and vertical transmission all involve processes that use CCR5 as a coreceptor for primary HIV-1 infection. Therefore, blocking the CCR5 receptor may provide an additional strategy to prevent HIV-1 vertical transmission.

Amniotic fluid composition in the fetal lamb with intrauterine growth restriction.

OBJECTIVE: Our aim was to examine changes from normal in the composition of amniotic fluid in fetal lambs with mild and severe hypoxemia and intrauterine growth restriction. STUDY DESIGN: Pregnant sheep underwent maternal catheterization at 88 to 93 days' gestation and fetal catheterization at 105-112 days' gestation. Twelve pregnancies (group 1) provided control data (fetal PaO 2 18-22 mm Hg), in 12 fetuses (group 2) mild hypoxemia (PaO 2 16-19 mm Hg) was induced by prevention of the normal expansion of maternal blood volume, and in 7 fetuses (group 3) chronic hypoxemia (PaO 2 12-18 mm Hg) developed spontaneously. RESULTS: In group 2 amniotic fluid osmolality and sodium concentrations were lower (approximately 30 mOsm/kg and 10 mEq/L, P <.05) and urea nitrogen level was higher (10 mg/dL, P <.05) than in group 1. In group 3 osmolality and sodium concentrations at approximately 120 days' gestation were similar to those in group 1. Whereas these values decreased with gestation in groups 1 and 2 (P <.05), they remained unchanged or increased in all fetuses in group 3. Mortality rates in groups 1, 2, and 3 were 1 of 12, 4 of 12 (difference not significant), and 5 of 7 (P <.05), respectively. CONCLUSION: Absence of normal decrease in amniotic fluid osmolality with gestation, in association with a high perinatal mortality rate, was found in severely but not in mildly hypoxemic fetuses with intrauterine growth restriction.

Implications of the kinetics of zidovudine in the pregnant baboon following oral administration.

Zidovudine (ZDV) therapy in pregnancy reduces mother-to-child transmission of HIV. The action of ZDV in the fetus is thought to be an important contributor to efficacy. Previous research in primates has demonstrated that continuous infusion of ZDV to the mother leads to sustained plasma concentrations in the fetus; however, it has not been determined what concentrations of ZDV are achieved in the fetus following oral administration. The pharmacokinetics of drug distribution to the fetus following oral administration of a 100-mg dose of ZDV to the mother are reported from 6 chronically catheterized baboons. The first order elimination half-life of ZDV from both the mother and fetus was approximately 1.2 hours. The area under the concentration-time curve for the fetus was 77% (r2 = 0.98; p < .001) that of the mother and the estimated peak drug levels in the fetus were 52% (r2 = 0.83; p < .01) those in the mother. The rapid transfer and short half-life of ZDV leads to a drug concentration-time profile that would not sustain levels in the fetus with dosing every 4 hours. After comparing these findings with existing data from pregnant and nonpregnant humans, it seems likely that current dose recommendations for ZDV in pregnancy would not maintain levels of the active intracellular metabolite of ZDV in all fetuses. This may explain in part the 8% failure rate of ZDV prophylaxis. The correlation between fetal and maternal plasma concentrations of ZDV would allow titration of dose based on maternal drug levels to achieve fetal levels within the therapeutic range.

Placental transfer and fetal metabolism of zidovudine in the baboon.

Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether the metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady-state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (+/-SE) fetal to maternal ratio of AZT was < 1 (0.84 +/- 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 +/- 49 mL/min and placental clearance was 36 +/- 4 mL/min, or approximately 5% of maternal clearance. Fetal clearance of AZT was estimated at approximately 15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT-glu in the fetus was 7.0 +/- 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.

Fetal cardiorespiratory and neurobehavioral response to zidovudine (AZT) in the baboon.

OBJECTIVE: To evaluate the effects of intravenous of zidovudine (AZT) at a dose and duration of infusion comparable to that used clinically on parameters reflective of fetal well-being. METHODS: Thirteen chronically instrumented noninfected baboons were monitored during intravenous infusions of AZT. Fetal cardiorespiratory activity and neurobehavioral function were assessed with 4-48-hour infusion of AZT to ten mothers (0.5-2.1 mg/kg per hour) and three fetuses (2-6 mg/h), which resulted in fetal plasma concentration of AZT of 194-3100 ng/ml. RESULTS: No significant differences were found in the mean values in control periods, before and after infusion with values during infusion for parameters of fetal heart rate and rate variability (n = 7), breathing activity (n = 8), electroencephalographic activity (n = 8), and behavioral state (N = 7). No correlations were found with drug level. CONCLUSIONS: The absence of associations between exposure of the fetal baboon to AZT and changes in parameters reflective of fetal condition suggests that comparable exposure of the human fetus during intravenous infusion of drug would not confound clinical monitoring used to assess fetal well-being. These findings supplement conclusions from clinical research in support of U.S. Public Health Service recommendations that intrapartum fetal monitoring be performed as clinically indicated, not specifically because pregnant patients are treated with intravenous AZT.

Effect of zidovudine on blood composition of the pregnant and fetal baboon.

OBJECTIVE: Our purpose was to assess the effect of intravenous zidovudine on placental function and fetal well-being. STUDY DESIGN: Eighteen chronically instrumented third-trimester pregnant baboons and their fetuses were studied after 4- to 48-hour infusions of zidovudine to 14 mothers (0.8 to 2.0 mg/kg/hr) and 6 fetuses (0.2 to 0.22 mg/kg/hr of maternal weight). Fetal and maternal pH and blood gases, hematocrit, blood cell counts, clinical chemistries, electrolytes, and hormones were measured before and after the infusions. RESULTS: In both mother and fetus no significant differences were found between values in the control periods and those after infusions of zidovudine in any of the index values measured. CONCLUSION: Administration of zidovudine from 4 to 48 hours in the baboon was associated with no significant change in any biochemical index values in the mother or fetus. Thus comparable exposure of the human fetus to zidovudine during labor is not expected to affect these index values of placental function and fetal well-being.

Maternal serum vitamin A levels are not associated with mother-to-child transmission of HIV-1 in the United States.

HIV-1 transmission from mother to child has been associated with maternal vitamin A status in studies of women living in Africa. This finding has raised the question of whether vitamin A supplementation might help reduce transmission in the United States as well as worldwide. In industrialized nations, however, both the vitamin A nutritional status of HIV-1-infected pregnant women and the association of vitamin A levels with vertical transmission were unknown. Furthermore, vitamin A is teratogenic, and supplements during pregnancy have caused birth defects. To investigate whether maternal serum levels of vitamin A (retinol) and three other micronutrients correlate with vertical transmission of HIV-1 in the United State, we studied 95 HIV-1-infected pregnant women and followed their infants to determine whether transmission occurred. Sera were obtained during the third trimester of pregnancy from 95 HIV-1-infected women living in the New York and Los Angeles metropolitan areas. The two cohorts were established to study vertical transmission of HIV-1 and to reflect the racial, ethnic, and socioeconomic status of HIV-1-infected in women in the United States. We measured serum levels of vitamin A (retinol) and three other micronutrients, vitamin E (alpha-tocopherol), beta-carotene, and lycopene, in the mothers using reverse-phase high-performance liquid chromatography and determined the HIV-1 infection status of their infants using virus cultivation and polymerase chain reaction. Sixteen of the 95 women transmitted HIV-1 to their infants. Statistical analysis of the data indicated that low maternal serum retinol levels during the third trimester of pregnancy were not associated with mother-to-child transmission of HIV-1. None of the women had retinol levels so low as to have clinical symptoms of vitamin A deficiency. The serum levels of alpha-tocopherol, beta-carotene, and lycopene, three micronutrients that act as antioxidants and enhance immune function, were also measured. Statistical analysis of the data revealed no association of the levels of these three micronutrients with vertical transmission of HIV-1. Analysis of the data obtained from 95 women in the United States indicates that vitamin A deficiency is rare, and serum retinol levels are not associated with risk of vertical HIV-1 transmission. In view of the teratogenic effects of vitamin A when taken as a supplement during pregnancy, pregnant HIV-1-infected women living in nations where vitamin A deficiency is not a public health problem should not be advised to take extra vitamin A supplements.

Testing cord blood human chorionic gonadotropin as a surrogate marker for early identification of human immunodeficiency virus-1 infection in children.

We measured human chorionic gonadotropin (hCG) in cord sera of 22 infants born to women infected with the human immunodeficiency virus-1 (HIV-1). hCG was also determined in cord sera from 173 infants born at a suburban hospital to HIV-1-seronegative women. The findings indicate that 16 (9%) of 173 HIV-1-seronegative samples had hCG levels greater than 90 IU/L (values were distributed as a Poisson curve). In contrast, 8 (36%) of the 22 infants born to HIV-1-infected women had hCG levels in excess of 90 IU/L, and 7 (88%) of these were shown to be HIV-infected. The remaining 14 infants born to HIV-1-infected women had low hCG levels, and 3 (21%) of the 14 had HIV infection. Mean follow-up time for HIV-uninfected infants was 17.5 months (range 9 months to 3 years). A statistically significant association between maternal-fetal HIV-1 transmission and hCG levels > or = 90 IU/L in cord sera was observed (p = 0.02). The difference between CD4 counts among mothers who transmitted HIV and those who did not was also statistically significant (p = 0.025). On the basis of this study's findings, we propose that cord blood hCG may serve as a surrogate marker for HIV-1 infection. Testing hCG levels in cord sera is an inexpensive and readily available screening test for early identification of infants at increased risk for getting HIV-1 from their mothers.

Blood pressure and HR in the fetal lamb: relationship to hypoglycemia, hypoxemia, and growth restriction.

We examined blood pressure and heart rate (HR) in relation to glucose and arterial PO2 (PaO2) at approximately 121 days (early) and at approximately 140 days (late) gestation in 12 growth-restricted and 10 control fetal lambs. Mild growth restriction (relative to maternal weight) was produced by withdrawal of 25 ml/day of maternal blood during the second half of pregnancy (P < 0.05). Fetuses from this model are hypoglycemic during early and late gestation but hypoxemic only during late study. Mean systolic and diastolic pressures in the experimental group were approximately 8.0 mmHg lower than the corresponding values in controls at both studies (P < 0.05). Fetal HR (FHR) was 15.4 beats/min lower (P < 0.05) in 10 but was higher than control in 2 experimental fetuses that were also not growth restricted. There were significant correlations between late systolic pressure and HR and PaO2 (r = 0.54, P = 0.046 and r = 0.50, P = 0.049, respectively) and between FHR and blood pressure and birth weight/maternal weight (P < 0.05). We conclude that, in this model, fetal blood pressure and HR may serve as good indicators of hypoxemia and growth restriction.

Zidovudine kinetics in the pregnant baboon.

The devastating impact of human immunodeficiency virus (HIV) infection during pregnancy has made the pharmacologic evaluation of potentially therapeutic agents of high priority. The results presented here are the maternal pharmacokinetics from a series of experiments to delineate more clearly the complex maternal-fetal pharmacokinetics and the effects of AZT in the chronically instrumented maternal and fetal baboon during both steady state intravenous infusion and oral bolus dosage regimens. Two results of major clinical importance were found. First, during pregnancy, both the clearance and volume of distribution of AZT were increased. Plasma clearance in the pregnant animals was 51 +/- 10 ml/min/kg compared with 37 +/- 2 ml/min/kg in the nonpregnant animals, and steady state volume of distribution was 3.7 +/- 1.21/kg compared with 2.2 +/- 0.61/kg. Second, with continuous intravenous infusion plasma drug concentrations were easily maintained in the therapeutic range, whereas with oral administration plasma concentration fell below therapeutic levels within 2 h of the dose being given. Because maternal plasma concentrations are a major determinant of drug concentration achieved in the fetus, an understanding of drug kinetics in pregnancy is of vital importance when making recommendations regarding optimal drug therapy during pregnancy to maximize the beneficial effect--the prevention of HIV infection in children.

Maternal plasma human immunodeficiency virus type 1 RNA level: a determinant and projected threshold for mother-to-child transmission.

To prevent mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission, it is important to identify its determinants. Because HIV-1 RNA levels can be reduced by antiviral therapy, we examined the role of maternal plasma HIV-1 RNA level in mother-to-child transmission. We used quantitative competitive PCR to measure HIV-RNA in 30 infected pregnant women and then followed their infants prospectively; 27% of the women transmitted HIV-1 to their infants and maternal plasma HIV-1 RNA level correlated strikingly with transmission. Eight of the 10 women with the highest HIV-1 RNA levels at delivery (190,400-1,664,100 copies per ml of plasma) transmitted, while none of the 20 women with lower levels (500-155,800 copies per ml) did (P = 0.0002). Statistical analysis of the distribution of HIV-1 RNA loads in these 30 women projected a threshold for mother-to-child transmission in a larger population; the probability of a woman with a viral RNA level of < or = 100,000 copies per ml not transmitting is predicted to be 97%. Examination of serial HIV-1 RNA levels during pregnancy showed that viral load was stable in women who did not initiate or change antiviral therapy. These data identify maternal plasma HIV-1-RNA level as a major determinant of mother-to-child transmission and suggest that quantitation of HIV-1 RNA may predict the risk of transmission.

Concentrations of corticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia.

The effect of pre-eclampsia on concentrations of corticotrophin releasing hormone (CRH) in umbilical-cord blood of fetuses at delivery was studied in order to determine if fetal CRH is elevated in this disorder when compared with uncomplicated pregnancy. Placental CRH may be a regulator of fetal pituitary-adrenal function and we therefore also measured ACTH, cortisol and dehydroepiandrosterone sulfate (DHEAS) in the umbilical-cord blood. The mean umbilical-cord plasma CRH in the fetuses from pregnancies complicated by pre-eclampsia, 667 +/- 153 pg mL-1, was significantly higher than the plasma CRH in the fetuses from normotensive pregnancies, 185 +/- 22 pg mL-1 (P < 0.001). The mean fetal cortisol concentration was significantly higher in pre-eclampsia, than in the normotensive, pregnancies (pre-eclampsia, 13.5 +/- 1.8; normotensive, 7.6 +/- 1.3 micrograms dL-1; P < 0.001). Plasma DHEAS was 217 +/- 23 micrograms dL-1 in the umbilical-cord blood of the fetuses from pregnancies complicated by pre-eclampsia and 281 +/- 35 micrograms dL-1 in the normotensive pregnancies (P < 0.01). Placental CRH synthesis and release, in contrast to hypothalamic CRH, appears to be stimulated by glucocorticoids. In pregnancies complicated by uteroplacental insufficiency, as may occur in pre-eclampsia, placental CRH production may be enhanced by increased fetal glucocorticoids. In turn, placental CRH may modulate fetal pituitary-adrenal steroidogenesis to favour increased cortisol secretion. Thus, placental CRH may play an important role in the fetal response to a compromised intrauterine environment.

Fetal hiccups in the baboon.

Bouts of hiccuping are recognized by pregnant women as distinct episodic movements of their fetuses. Ultrasound imaging of these fetuses has documented the occurrence of hiccups from early gestation through parturition. This study provides a systematic characterization of prenatal hiccuping in the fetal baboon (Papio species). Tracheal fluid pressure was recorded from 11 chronically instrumented fetal baboons for 21.5 +/- 7.3 consecutive days (mean +/- SD) over a range in gestation from 124 to 164 days (term 175 days). In an initial review of pressure recordings by visual inspection, hiccups were recognized as distinctive high-amplitude fluctuations in tracheal pressure that were readily discriminated from fetal breaths. Automated techniques were then developed and validated to detect hiccups and summarize their features. The mean hiccup amplitude was 23.0 +/- 3.1 mmHg, inspiratory time was 0.26 +/- 0.03 s, and expiratory time was 0.27 +/- 0.02 s. Each of these features discriminated hiccups from breaths (P < 0.001). Hiccuping incidence (1.8 +/- 0.4% of time), rate (26.2 +/- 6.2 min-1), bout duration (4.3 +/- 0.8 min), and the interval between bouts (3.35 +/- 0.60 h) were also different (P < 0.01) from breathing. These features of hiccups remained relatively constant over the latter third of gestation with the exception of an increase in duration of the expiratory time interval (r = 0.54, P < 0.01). Despite their vigorous nature, bouts of hiccuping were not associated with transitions in behavioral state. Moreover, the features of hiccups were not differentiated by state. Bouts of hiccuping recurred in a cyclic fashion, on average every 3-4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of human immunodeficiency virus type 1 during pregnancy: relationship of viral titer to mother-to-child transmission and stability of viral load.

To develop strategies to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1), it is important to define the factors determining it. We examined the relationship between maternal HIV-1 titer and the occurrence of mother-to-child transmission. In addition, we quantitated HIV-1 longitudinally in mothers during pregnancy, at delivery, and up to 1 year postpartum. To examine transmission, we prospectively studied 19 mother-child pairs; in 5 pairs, HIV-1 transmission occurred. We used endpoint dilution culture of peripheral blood mononuclear cells to determine maternal viral titer and found that although 4 of 6 (67%) women with viral titers of > or = 125 HIV-1 infectious units per 10(6) cells transmitted HIV-1 to their infants, only 1 of 13 (7.6%) women with lower viral titers transmitted (P = 0.01). Twelve of the 19 mothers had HIV-1 loads determined serially 3-8 times over periods ranging from 18 to 65 weeks. Viral titers varied greatly between the 12 women, but the viral load in each woman remained stable over time. In this cohort, HIV-1 viral load remained stable during pregnancy and the greater the maternal viral burden, the more likely that transmission occurred. These two related findings suggest that determination of HIV-1 titers early in pregnancy may predict which women are at high risk of transmitting to their infants and may be used to counsel HIV-1-infected women of childbearing age. These data identify maternal viral titer as a major determinant of mother-to-child HIV-1 transmission and thereby provide the scientific rationale for therapeutic strategies designed to interrupt transmission by lowering viral load.

Patterns of fetal breathing in the baboon vary with EEG sleep state.

This report examines the hypothesis that the characteristics of breathing activity of the fetal baboon are modulated with respect to sleep state in a fashion similar to that observed in the human fetus. The pattern of fetal breathing activity was examined in relationship to electroencephalographic (EEG) sleep state in studies of six fetuses of chronically monitored pregnant baboons at 143-148 days of gestation (term, 175-180 days). Fetal breaths were defined by fluctuations of tracheal fluid pressure. EEG sleep states were defined with an automated method for discrimination of EEG patterns that are standard indices of quiet and active sleep in immature primates. During more than 250 h of recorded data, the fetuses spent on average 33.3 +/- 3.9% of time in EEG quiet sleep. In comparisons across state the fetuses spent significantly (P = 0.001) less time breathing during quiet than active sleep (49.5 +/- 6.8 vs. 69.0 +/- 3.8%). The inspiratory and expiratory time intervals of fetal breaths were not differentiated by EEG state but, the mean breath to breath interval was significantly (P < 0.001) longer in EEG quiet sleep. In addition to these differences in incidence and time interval of breaths, during epochs of breathing, there was a significantly slower rate, lower amplitude, and lower variability of rate of breathing in quiet sleep (all P-values < 0.02). Thus, periodic breathing activity in the fetal baboon is present in both quiet and active EEG sleep states. Sleep states have a powerful influence on patterns of fetal breathing in the non-human primate, directly comparable to the human fetus.

Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses.

CRH is synthesized in the hypothalamus and released in response to stress into the portal hypophyseal blood; an additional site of synthesis, the placenta, is present only during pregnancy. Placental CRH is released into the maternal and fetal circulation during human pregnancy, and we hypothesized that the chronic fetal stress associated with fetal growth retardation may stimulate placental CRH release. We measured plasma CRH concentrations in the umbilical cord blood of 28 growth-retarded fetuses and 28 normally grown fetuses matched for gestational age and mode of delivery. Plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol were also measured in the umbilical cord samples to determine if CRH levels were correlated with levels of pituitary and adrenal hormones. The mean umbilical cord plasma CRH level in the growth-retarded fetuses was 206 +/- 25.8 pmol/L, which was significantly higher than that in the normally grown fetuses matched for gestational age, presence or absence of labor, and mode of delivery (49.4 +/- 16.7 pmol/L; P < 0.01). The mean plasma ACTH level in the growth-retarded fetuses (5.7 +/- 1.2 pmol/L) was significantly higher than that in the normally grown fetuses (3.3 +/- 0.7 pmol/L; P < 0.05). The mean cortisol concentration in the growth-retarded fetuses was 260 +/- 32.5 nmol/L, and that in the normally grown fetuses was 220 +/- 40 nmol/L. The mean DHEAS level was significantly lower in the growth-retarded fetuses (4.8 +/- 0.6 mumol/L) than that in the normally grown fetuses (7.7 +/- 0.6 mumol/L; P < 0.001). There was a significant correlation between umbilical cord plasma CRH and both ACTH and cortisol concentrations as well as a significant negative correlation between CRH and DHEAS levels in the growth-retarded fetuses. The umbilical cord plasma CRH level is extremely elevated in growth-retarded fetuses compared to that in normal fetuses. Placental CRH, like hypothalamic CRH, may be stimulated in conditions of chronic stress and may modulate fetal pituitary-adrenal function in high risk pregnancies.

Patterns of development in fetal breathing activity in the latter third of gestation of the baboon.

Patterns of fetal breathing activity were examined in a longitudinal study of the fetal baboon over the latter third of gestation. More than 1400 h of recorded tracheal fluid pressure in 16 or 24 h records from seven fetuses over a range in gestation from 121 to 172 days (term, 175-180 days) were analyzed. In these 81 records, there was a high degree of variability in the percent of time spent breathing by the fetuses (range, 14-83%) with no apparent influence of gestational age (mean +/- S.D., 45.6 +/- 17.6%). Nonetheless, the mean amplitude of fetal breaths increased with gestation from absolute values of about 5-10 mmHg (r = 0.73, P < 0.001) and the mean inspiratory time interval increased from about 0.45-0.55 s (r = 0.40, P < 0.001). During epochs of breathing, the mean rate decreased from about 42-36 breaths per min (r = -0.54, P < 0.001) and the indices of both short term (r = -0.54, P < 0.001) and long term (r = -0.73, P < 0.001) variability in rate decreased. These results demonstrate a clearly defined pattern of development in the breathing activity of the fetal baboon which is comparable to the pattern described for the human fetus in the third trimester of gestation. These similarities suggest that the progressive functional maturation of the mechanisms generating respiratory patterns are comparable among primate species.

Corticotropin releasing hormone concentrations in umbilical cord blood of preterm fetuses.

Corticotrophin releasing hormone (CRH), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured in umbilical cord plasma obtained from 90 preterm and 98 term fetuses. Maternal plasma was obtained from 23 women who delivered preterm and from 23 women matched for gestational age who ultimately delivered term infants. Mean umbilical cord plasma CRH concentration was significantly higher in the preterm fetuses (n = 69, 538 +/- 63 pg/ml) compared to the term fetuses (n = 98, 280 +/- 22 pg/ml, P < 0.01). Mean DHEAS level in the preterm fetuses was 208 +/- 22 mg/dl (n = 56), cortisol level was 7 +/- 1 mg/dl (n = 58). Umbilical plasma CRH concentrations (808 +/- 170 pg/ml) were significantly higher at 24-27 weeks than at 28-31 or 31-34 weeks gestation. Cortisol levels (12 +/- 3 micrograms/dl) were highest at 24-27 weeks. Mode of delivery and the presence of labor did not affect fetal CRH levels. The highest fetal CRH levels were measured in the pregnancies complicated by hypertension as well as prematurity; however, fetal CRH levels remained higher in the preterm group compared to the term group when hypertensive pregnancies were excluded. Maternal plasma CRH levels were significantly higher in the group that delivered preterm compared to women who delivered at term matched for gestational age (1058 +/- 184 pg/ml compared to 456 +/- 71 pg/ml, P < 0.00).(ABSTRACT TRUNCATED AT 250 WORDS)