Neonatal infant EEG bursts are altered by prenatal maternal depression and serotonin selective reuptake inhibitor use.

OBJECTIVE: Increasingly, serotonin selective reuptake inhibitor (SSRI) medications are prescribed in pregnancy. These medications pass freely into the developing fetus but little is known about their effect on brain development in humans. In this study we determine if prenatal maternal depression and SSRI medication change the EEG infant delta brush bursts which are an early marker of normal brain maturation. METHODS: We measured delta brush bursts from the term infants of three groups of mothers (controls (N = 52), depressed untreated (N = 15), and those taking serotonin SSRI medication (N = 10). High density EEGs were obtained during sleep at an average age of 44 weeks post conceptional age. We measured the rate of occurrence, brush amplitude, oscillation frequency and duration of the bursts. RESULTS: Compared to infants of control mothers, the parameters of delta brush bursts of the offspring of depressed and SSRI-using mothers are significantly altered: burst amplitude is decreased; the oscillation frequency increased, and the duration increased (SSRI only). These significant differences were found during both sleep states. CONCLUSIONS: Electrocortical bursting activity (i.e. delta brushes) is known to play an important role in early central nervous system (CNS) synaptic formation and function. SIGNIFICANCE: Maternal depression or SSRI use may alter brain function in their offspring.

Family Nurture Intervention in preterm infants alters frontal cortical functional connectivity assessed by EEG coherence.

AIM: To assess the impact of Family Nurture Intervention (FNI) on cortical function in preterm infants at term age. METHODS: Family Nurture Intervention is a NICU-based intervention designed to establish emotional connection between mothers and preterm infants. Infants born at 26-34 weeks postmenstrual age (PMA) were divided into two groups, standard care (SC, N = 49) and FNI (FNI, N = 56). Infants had EEG recordings of ~one hour duration with 124 lead nets between 37 and 44 weeks PMA. Coherence was measured between all pairs of electrodes in ten frequency bands. Data were summarised both within and between 12 regions during two sleep states (active, quiet). RESULTS: Coherence levels were negatively correlated with PMA age in both groups. As compared to SC infants, FNI infants showed significantly lower levels of EEG coherence (1-18 Hz) largely within and between frontal regions. CONCLUSION: Coherence in FNI infants was decreased in regions where we previously found robust increases in EEG power. As coherence decreases with age, results suggest that FNI may accelerate brain maturation particularly in frontal brain regions, which have been shown in research by others to be involved in regulation of attention, cognition and emotion regulation; domains deficient in preterm infants.

Developmental profiles of infant EEG: overlap with transient cortical circuits.

OBJECTIVE: To quantify spectral power in frequency specific bands and commonly observed types of bursting activities in the EEG during early human development. METHODS: An extensive archive of EEG data from human infants from 35 to 52 weeks postmenstrual age obtained in a prior multi-center study was analyzed using power spectrum analyses and a high frequency burst detection algorithm. RESULTS: Low frequency power increased with age; however, high frequency power decreased from 35 to 45 weeks. This unexpected decrease was largely attributable to a rapid decline in the number of high frequency bursts. CONCLUSIONS: The decline in high frequency bursting activity overlaps with a developmental shift in GABA's actions on neurons from depolarizing to hyperpolarizing and the dissolution of the gap junction circuitry of the cortical subplate. SIGNIFICANCE: We postulate that quantitative characterization of features of the EEG unique to early development provide indices for tracking changes in specific neurophysiologic mechanisms that are critical for normal development of brain function.

Reduced functional connectivity in visual evoked potentials in children with autism spectrum disorder.

OBJECTIVE: An analysis of EEG synchrony between homologous early visual areas tested the hypothesis that interhemispheric functional connectivity during visual stimulation is reduced in children with autism compared to controls. METHODS: EEG power and coherence within and between two homologous regions of the occipital cortex were measured during long latency flash visual evoked potentials. Measures were compared between two groups of children (5.5-8.5years), one with autism spectrum disorders and the other with typical development. RESULTS: In and below the theta band, interhemispheric synchrony was reduced in autistic subjects compared to typical controls by as much as 50%. Above the theta band interhemispheric synchrony in autistic children became indistinguishable from what would occur for uncorrelated cortical activity. Interhemispheric synchrony in autistic subjects was decreased in spite of bilaterally increased power. Wavelet power showed autistic children had a more rapid initial response to stimulation, a slower recovery, and more modulation at longer latencies. CONCLUSIONS: Results suggest that the sensory cortices of autistic children are hypersensitive to stimulation with concurrent diminished functional connectivity between hemispheres. SIGNIFICANCE: Simultaneously increased intrahemispheric power and decreased interhemispheric synchronization of elementalvisual information suggests either that power increases cause poor interhemispheric connectivity or that processes, such as thalamocortical regulation, impact power and coherence independently.

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.

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.

Gestational age related changes in cardiac dynamics of the fetal baboon.

To provide insight into the maturation of neural mechanisms governing fetal heart rate and rate variability, seven chronically instrumented fetal baboons were monitored under steady state conditions between 120 and 165 days gestation (term 175 d). Forty records of 24 h duration (5-7 records/fetus) were evaluated. For each fetus, heart rate decreased with gestational age (mean+/-SD, r = -0.530+/-0.324, P <0.05). In contrast, there were increases with age in markers of various components of autonomic control of fetal R-wave to R-wave interval (RRi) variability as reflected in a positive correlation with age for all fetuses of SD RRi (r = 0.656+/-0.347, P < 0.01), root mean squared differences in RRi (r = 0.686+/-0.223, P <0.05), and power at low frequency in the RRi spectrum (r = 0.800+/-0.161 P < 0.01). In each of the seven fetuses, scatter plots of RRi as a function of the prior RRi (Poincare plots) had increased dispersion around the median with gestational age (0.605+/-0.371, P<0.05). Additional measures of variability evaluated changes in RRi from one interval to the next (deltaRRi). The incidence of sustained deltaRRi changes, either decelerations or accelerations, rose with gestation (r = 0.920+/-0.057, P < 0.001) while the incidence of no detected deltaRRi changes (<+/-1 ms) diminished (r = - 0.649+/-0.364, P <0.05). Sequential decreases in fetal heart rate, increases in RRi variability and increases in changes in RRi and deltaRRi with age imply an overall maturation in autonomic cardio-regulatory control processes. Increases with gestation in measures of high frequency components of variability are compatible with enhanced parasympathetic modulation of fetal heart rate.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.