Biomedical subjects

R I Stark

Publications and source records attributed to R I Stark.

At least 19 recordsLinked to original sources

PubMed1998

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.

Administration, Oral↗

PubMed1998

Effects of sleeping position and time after feeding on the organization of sleep/wake states in prematurely born infants.

Epidemiologic studies provide strong evidence for the conclusion that sleeping in the prone position places infants at greater risk for sudden infant death syndrome (SIDS). Prior studies in newborn infants found that in the prone sleeping position there is less time awake and more quiet sleep, but little change in the amount of active sleep. To determine whether the effects of sleeping position on state distribution vary with time after feeding, we studied prematurely born infants in both the prone and supine sleeping positions. Sleep states were recorded each minute during interfeed intervals. Results demonstrate expected effects of sleep position on state distribution: prone sleeping is associated with a 79% increase in quiet sleep and a 71% decrease in time awake. While the decreases in time awake are seen throughout the interfeed interval, increases in quiet sleep in the prone position are found only within the first hour and again near the end of the interfeed interval. These results are consistent with the hypothesis that prone sleeping could increase risk for SIDS by altering the organization of sleep, and that time after feeding may play an important role in the expression of these effects.

Analysis of Variance↗

PubMed1998

Diurnal rhythm of fetal behavioral state.

To test for the presence in utero of diurnal periodicity in the amount of time spent in organized behavioral states, seven records of 24-hour duration were obtained from each of five chronically instrumented fetal baboons between 144 and 158 days gestation (term = 175 days). Concordance of fetal breathing activity, heart-period variability, and electroencephalographic parameters were used to define two distinctive patterns of fetal physiological activities. One pattern was characterized as EEG activity dominated by tracé alternant, reduced heart-period variability, and fewer breaths in epochs of fetal breathing. This fetal behavioral state (1FB) is analogous to quiet sleep in infants. A second pattern was characterized by the relative absence of tracé alternant, increased heart-period variability, and fetal breathing activity. This fetal behavioral state (2FB) is analogous to active sleep. Cycles of these states were present 29% of time, with a duration of approximately 26 minutes and a 1.7:1 predominance of 2FB/1FB. Cosinor analysis across fetuses revealed a significant (p < .01) 24-hour periodicity of the time spent by the fetus in organized behavioral states, with a peak around 1400 (lights-on 0700 to 1900) and a peak-nadir fluctuation of 15%. These periodicities in the incidence of organized state were significant (p < .01) in three fetuses, and approached significance (< .09) in the two others. Data demonstrate a diurnal rhythmicity in fetal behavioral states, with less time spent in organized state at night than during the day.

Animals↗

PubMed1998

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.

Amniotic Fluid↗

PubMed1997

A novel quantitative measure of Tracé-alternant EEG activity and its association with sleep states of preterm infants.

This study describes the application of a novel quantitative method for classifying patterns of EEG activity that are associated with the predominant sleep-states of newborn infants. Periods in which there are bursts of high-voltage slow wave activity in the EEG that alternate with periods of low-voltage activity are termed Tracé-alternant. During active or REM sleep. Tracé-alternant is absent and EEG activity is characterized by a variable mixture of frequencies including intermittent high frequency (10-20 Hz) activity superimposed on slower frequencies. Results show that an analytic method previously developed in fetal baboons for identifying EEG segments with and without Tracé-alternant successfully distinguishes homologous patterns of EEG activity in preterm infants. This method provides an excellent objective approach for monitoring changes in EEG patterns that are coincident with behaviorally defined sleep states.

Animals↗

PubMed1997

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.

Acid-Base Equilibrium↗

PubMed1996

Diurnal rhythms in cardiorespiratory function of the fetal baboon.

Diurnal periodicities of cardiorespiratory function were monitored between 144 and 156 days of gestation (term = 175 days) in six chronically instrumented fetal baboons. For each fetus, 5-11 days of electrocardiographic and tracheal fluid pressure data were summarized as hourly means of fetal heart rate (FHR), standard deviation of FHR, breath-to-breath interval (B-Bi) and percent time spent in fetal breathing activity (PFB). Summaries were evaluated by cosinor analysis to determine the least squares fit to a 24-h cycle. For all fetuses, FHR had a significant (P < 0.001) diurnal rhythm with peak to nadir fluctuations of 17.4 beats/min around a 24-h mean of 163.2 beats/min. The time of the peak FHR was similar across animals occurring in the mid-day between 10:49 h and 14:45 h. For each fetus, standard deviation of FHR also had a significant (P < 0.01) diurnal periodicity with highest values at night between 20:15 h and 02:04 h. The times of the acrophase for these heart rate parameters were correlated (R = 0.88, P < 0.02) across fetuses. Significant (P < 0.001) 24-h rhythms were found in four of six fetuses for B-Bi and five of six for PFB. These PFB rhythms accounted for a fluctuation of 14.4% around a mean of 36.9 +/- 4.5%. In contrast to heart rate, the acrophases of fetal breathing parameters were distributed throughout the entire 24-h cycle and not significantly correlated across fetuses. It is concluded that diurnal rhythms of fetal heart rate, which are synchronized with light/dark conditions in the environment, are evidence for a passive response or entrainment of fetal systems to maternal circadian influences. Alternately, the absence of synchronization across fetuses in daily rhythms of fetal breathing activity provides evidence for a functioning fetal pacemaker, and not simply the imposition of maternal rhythms on her fetus. This differential in the cardiac and breathing activity of the developing primate indicates that pathways for entrainment of fetal pacemaker function are subject to important maturational influences during late gestation.

Animals↗

PubMed1996

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.

Absorption↗

PubMed1996

Patterns of perinasal fluid flow and contractions of the diaphragm in the human fetus.

Our aim was to identify patterns of fetal perinasal fluid flow, and to determine the relationship of pattern of flow to the diaphragmatic component of fetal breathing movements. Twenty-four fetuses were studied with the use of two ultrasound systems simultaneously. Continuous video-tape records of the color and spectral Doppler imaging of fluid flow velocity in the nose and of the movements of the fetal diaphragm were made on two video recorders during 30-min study sessions. Two different patterns of fetal perinasal flow were recognized. One type had a rapid rate and low amplitude, and was independent of ultrasonographically observed movements of the fetal diaphragm. The other type had a lower rate and higher amplitude, and was uniformly related to diaphragmatic contractions. The breath-to-breath interval, time of inspiration, time of expiration and peak inspiratory and expiratory velocities were determined for each type of perinasal flow. Two ratios were used to quantify the change of peak flow velocity. There were significant differences in the values of all timing parameters between diaphragm-related perinasal flow velocities and those not related to the diaphragm, at both 30-36 and 37-41 weeks of gestation. The rate of perinasal flow related to diaphragmatic contraction cycles was one-third that of the flow cycles not related to diaphragmatic contraction (approximately 50 vs. 148 cycles/min). For both patterns of perinasal flow velocity, the expiratory peak velocity ratio was about 1.6 times higher than the inspiratory peak velocity ratio. We conclude that, in uncomplicated pregnancy, one pattern of fetal perinasal fluid flow reflects activity of the diaphragm. We speculate that the contractions of the fetal airway smooth muscle or oropharyngeal-laryngeal muscle groups are the origin of the second pattern of perinasal flow.

Blood Flow Velocity↗

PubMed1996

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.

Animals↗

PubMed1996

Iodine, thyroid function, and very low birth weight infants.

OBJECTIVE: Research was undertaken to test two hypotheses. First, during the early neonatal period, thyroid function of very low birth weight (VLBW) infants is suppressed by exposure to iodine-containing antiseptic solutions and/or iodized contrast media. Second, this suppression is more pronounced in small for gestational age (SGA) infants. METHODS: Urinary iodine concentration and thyroid function measurements were obtained prospectively from 44 VLBW infants with gestational ages at birth of 30 +/- 2.3 weeks and weights of 1223 +/- 231 g. Eleven of these infants were SGA. The infants were grouped according to iodine exposure: 18 infants had no increased exposure and served as control infants; 9 infants were exposed to an iodine-containing antiseptic (povidone iodine); 12 infants were exposed to an iodized contrast medium (iopamidol); and 5 infants were exposed to both agents. Urinary iodine and serum free triiodothyronine, free thyroxine, and thyrotropin were measured on days 1, 7, 14, 21, and 28 of life. RESULTS: During the period of maximum exposure (days 1 to 7), the concentration of iodine in the urine of study infants was 2 to 4 orders of magnitude greater than that in the urine of control infants (123 +/- 141 micrograms/L). During the subsequent 3 weeks, levels of urinary iodine in study infants returned to levels that were not significantly different from controls. On day 7 of life, iodine-exposed infants had a significantly higher mean thyrotropin level than control infants, whereas on day 28, free triiodothyronine and thyroxine levels were lower. Of the 26 iodine-exposed infants, 6 had transient hyperthyrotropinemia and 2 had transient hypothyroidism. When exposed to iodine, SGA infants had more labile thyroid function than normally grown iodine-exposed or control infants. These SGA infants had significantly lower levels of thyroid hormones in umbilical cord blood, increased production of thyroid hormones on day 14 of life, and lower levels again at 1 month. CONCLUSION: In VLBW infants, the use of iodine-containing antiseptic solutions and iodized contrast media results in massive uptake of iodine that is associated with alterations in thyroid function. It is reasonable to suggest that, whenever possible, iodized products should be avoided in VLBW infants, because their routine use results in exposure to excessive loads of iodine, which can be associated with hyperthyrotropinemia and hypothyroidism.

Anti-Infective Agents, Local↗

PubMed1995

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.

Adrenocorticotropic Hormone↗

PubMed1994

Behavioral states in the fetal baboon.

This study was designed to characterize behavioral states in the fetal baboon. Automated methods were developed and validated to recognize behavioral states based on relationships among three physiologic variables (EEG patterns, eye movements, heart period variability). Data included twelve 16-h records from 3 chronically instrumented fetal baboons at 0.8-0.9 of term. Randomly generated control records were used to differentiate occurrences of state from chance association of the variables. For 41.2 +/- 4.6% (mean +/- S.E.) of the time, the physiologic variables were synchronous and formed cycles of state with a mean duration of 34.4 min. Components of these cycles had mean +/- S.E. durations of 7.2 +/- 0.3 min for state 1FB (the analogue of quiet sleep in the human infant and state 1F in the human fetus), 20.7 +/- 1.2 min for the state 2FB (the analogue of active sleep in the human infant and state 2F in the human fetus), and 3.6 +/- 0.2 min for state transitions. For 24.6 +/- 2.4% of the time, the state variables exhibited coincidental, state-like agreements, that were not part of state cycles. Finally, for 34.3 +/- 2.7% of the time, there was no systematic agreement among the three variables. These data provide convincing evidence that organized behavioral states are present in the fetal baboon as early as 0.8 of term gestation.

Algorithms↗

PubMed1994

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.

Animals↗

PubMed1994

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)

Animals↗

PubMed1993

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.

Amniotic Fluid↗

PubMed1993

A quantitative method for classification of EEG in the fetal baboon.

Electroencephalographic (EEG) activity is used as a primary indicator of sleep states in adults and infants of many species and in the ovine fetus. We recently reported that the baboon fetus exhibits visually discernable patterns of EEG activity. One pattern of activity, characterized by the intermittent presence of repetitive bursts of high-voltage EEG, is indistinguishable from trace alternant (TA). TA is a distinctive pattern of EEG activity found only during early stages of development in primates. TA is the predominant pattern of EEG activity during quiet sleep in human infants < 2 mo of age. The focus of this study was to derive quantitative parameters that would discriminate TA from other activity and then to develop a method for automated categorization of EEG patterns. Results demonstrate that several parameters derived from frequency-domain analyses are related to visually coded EEG states. Among these parameters, high-frequency power (12-24 Hz) and spectral-edge frequency are good discriminators of EEG patterns. This paper describes a new parameter, EEG ratio, computed as spectral power in the rectified EEG within a band that corresponds to the frequency of bursts of activity during TA (0.03-0.20 Hz) divided by power in the 12- to 24-Hz band. This new composite parameter of EEG activity provides a markedly better correlate of visually coded EEG than any of the individual parameters tested. Using cluster analysis, we devised a method for objective minute-by-minute dichotomization of EEG ratio. The method produces results that agree with visual coding of EEG activity 87.1% of the time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

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.

Adrenocorticotropic Hormone↗