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.

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.

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)

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)

Prevention of the normal expansion of maternal plasma volume: a model for chronic fetal hypoxaemia.

The effects of inadequate expansion of maternal blood volume on uterine blood flow, fetal oxygen levels and vasoactive mediators during the third trimester were studied in 8 pregnant sheep. Results were compared to those obtained during 15 normal pregnancies. Prevention of the normal (20 ml/day) increase in maternal plasma volume was achieved by repeated haemorrhage and injections of furosemide. These treatments also reduced the rise in blood flow to the pregnant uterine horn that normally occurs during this period of gestation: at term flow was only 508 +/- 61 (SEM) compared to 838 +/- 83 ml/min in the control group (P greater than 0.01). This reduction in uterine blood flow caused a gradual fall in fetal PaO2, and rise in fetal levels of plasma renin activity, vasopressin, catecholamines and angiotensin II without change in pHa or base excess. Four to 5 days prior to delivery, the difference from control in PaO2 was -3.9 +/- 0.5 mmHg, plasma renin activity +2.9 +/- 1.7 ng/ml.h, vasopressin +4.2 +/- 1.1 pg/ml, catecholamines +957 +/- 145.3 pg/ml and angiotensin II +243 +/- 108.2 pg/ml. Furthermore, the fall in PaO2 and rise in vasoactive mediators that normally occur 3-5 days prior to the onset of labour was either absent (PaO2 and plasma renin activity) or blunted. Thus when expansion of blood volume during pregnancy is inadequate, blood flow to the uterus is adversely affected. This leads to various degrees of chronic fetal hypoxaemia and stimulation of vasoactive mediator systems. However, the normal stimulation of vasoactive mediator systems that occurs 3-5 days before delivery appears to be blunted. Experimental prevention of blood volume expansion during pregnancy produces an excellent model for the study of chronic mild fetal hypoxaemia.

Chronic instrumentation and longterm investigation in the fetal and maternal baboon: tether system, conditioning procedures and surgical techniques.

A tether system, conditioning procedures and surgical techniques were designed to maintain chronic catheters and electrodes in the pregnant baboon and her fetus. The tether system was comprised of a lightweight metal backpack containing catheters and electrodes, couplers, pressure transducers and electrical cabling. The backpack was held snugly in place by shoulder and body straps. A flexible metal tether connected the pack to a ball bearing assembly mounted on the top of the animal's home cage. Attached to the assembly were two infusion pumps, fluid reservoir and slip ring electrical connector. The entire system rotated freely with the movements of the animal; thus, the instrumentation and connectors were secure while access was maintained for continuous physiologic recording and intravascular infusion or intermittent blood sampling with minimal physical restraint. Animals were conditioned to accept the system prior to pregnancy and animals who demonstrated tolerance were bred. An initial group of 10 pregnant animals were sham tethered during pregnancy at 102 +/- 7 days with term gestation estimated at 180 days. Surgical procedures were done at 136 +/- 4 days with placement of catheters in the maternal femoral artery and vein, fetal carotid artery jugular vein and trachea, amniotic fluid cavity, and electrodes for fetal electrocardiogram and electroencephalogram. The mean fetal survival time was 9.3 (range 0 to 29) days. The major complications which led to early delivery were placental abruption and rupture of amniotic membranes. With ultrasonic localization of the placenta and determination of fetal position before surgery, these complications may be avoided.(ABSTRACT TRUNCATED AT 250 WORDS)

Biologically active corticotropin-releasing hormone in maternal and fetal plasma during pregnancy.

Corticotropin-releasing hormone was measured in the plasma of 110 pregnant women and in the umbilical cord plasma of 25 premature infants and 43 infants born at term. Mean maternal plasma corticotropin-releasing hormone was undetectable (less than 41 pg/ml) until mid-second trimester, rose to a mean of 204 +/- 24 pg/ml by 30 weeks' gestation, to 326 +/- 41 by 35 weeks, and then rose sharply near term, with a mean of 2930 pg/ml at 38 to 40 weeks' gestation. Sequential measurements in seven pregnant women confirmed that plasma corticotropin-releasing hormone rose in a predictable pattern, with a dramatic increase in the final weeks of pregnancy. There was little hour-to-hour variability in maternal plasma concentrations. Corticotropin-releasing hormone was also detectable in umbilical cord plasma; mean corticotropin-releasing hormone was 194 +/- 44 in the preterm infants and 150 +/- 19 in the term infants. The corticotropin-releasing hormone extracted from both the maternal and fetal circulation was biologically active in vitro and caused the dose-dependent release of adrenocorticotropic hormone and beta-endorphin from cultured rat anterior pituitary cells. A significant correlation was found between maternal plasma corticotropin-releasing hormone and cortisol levels the morning after betamethasone administration, a finding that supports a physiologic role for maternal plasma corticotropin-releasing hormone. We conclude that the placenta secretes large amounts of biologically active corticotropin-releasing hormone into both the maternal and fetal circulation during pregnancy. We demonstrate that this corticotropin-releasing hormone is secreted into the maternal plasma in a reproducible pattern during normal term pregnancy and suggest that sequential corticotropin-releasing hormone measurements may prove to be of clinical utility. In addition, placental corticotropin-releasing hormone may be an important modulator of the hypothalamic-pituitary-adrenal axis during pregnancy.

Effects of betamethasone on maternal plasma corticotropin releasing factor, ACTH and cortisol during pregnancy.

Corticotropin releasing factor immunoactivity (CRFi) has been identified in the plasma of women in the second half of gestation. There are several lines of evidence supporting a placental source for this hormone. Regulation of placental CRFi is poorly understood. In this study, the effect of a long-acting glucorticoid on the release of placental CRFi was investigated. Eleven women in the third trimester of pregnancy had plasma samples measured for CRFi, ACTH and cortisol before and after receiving 12 mg betamethasone. There was a significant decrease in ACTH (p less than 0.05) and cortisol levels (p less than 0.01) but no change in CRFi. It is concluded that the secretion of CRFi by the placenta is not inhibited by the administration of betamethasone while maternal levels of cortisol and ACTH are lowered. These results suggest that the acute regulation of placental CRFi is distinct from the regulation of hypothalamic CRF.

Cerebrospinal fluid and plasma vasopressin in the fetal lamb: basal concentration and the effect of hypoxia.

The concentrations of vasopressin in the plasma and cerebrospinal fluid (CSF) of the chronically catheterized fetal lamb were measured under basal and hypoxic conditions. Under basal conditions, samples were obtained from 13 fetal lambs of 117-146 days gestation. The mean +/- SEM vasopressin level in CSF was 19.5 +/- 1.5 pg/ml; the mean plasma vasopressin level of 1.9 +/- 0.2 pg/ml was significantly less (P less than 0.001). No consistent change in concentrations of vasopressin in CSF was observed with gestational maturation in 3 animals sampled sequentially or in individual samples obtained over the last 32 days of gestation. The mean vasopressin concentration in the CSF of the pregnant ewe was 5.1 +/- 0.4 pg/ml. The gradients for osmolality, sodium, and potassium between fetal plasma and CSF were: osmolality, 298.4 +/- 1.6 to 304.3 +/- 1.4 mosmol/kg; sodium, 140.9 +/- 0.5-142.5 +/- 0.5 meq/liter; and potassium, 4.3 +/- 0.1 to 3.3 +/- 0.1 meq/liter. Fetal hypoxia was induced by exposure of the ewe to 10% O2 in N2 for 30 min. The concentration of vasopressin increased from 1.7 +/- 0.3 to 277 +/- 144 pg/ml (P less than 0.001) in fetal plasma and from 21.4 +/- 3.8 to 47.1 +/- 9.9 pg/ml (P less than 0.04) in fetal CSF. When the ewe was exposed to room air under comparable experimental conditions, no similar changes in plasma or CSF vasopressin levels were observed in the fetus. Infusion of vasopressin into the fetal jugular vein at 1.0 mU/min for 30 min increased plasma concentrations from 2.3 +/- 0.5 to 83 +/- 17 pg/ml, while the CSF vasopressin values were 31.9 +/- 5.9 (basally) and 30.7 +/- 4.8 pg/ml (after infusion). Mean plasma and CSF osmolality, sodium, and potassium were not changed by any of these experimental interventions. We conclude that 1) under basal conditions, high concentrations of vasopressin are present in the CSF of the fetal lamb, the blood-CSF barrier appears to be impermeable to vasopressin, and concentrations of the hormone in fetal plasma are less than those in CSF; and 2) hypoxia is a potent stimulus of vasopressin release in both fetal plasma and CSF. The route of vasopressin released into the fetal CSF may be distinct from that released into plasma.

The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects.

We measured serum concentrations of calcium and parathyroid hormone in seven pregnant women who were receiving intravenous magnesium sulfate for the suppression of premature labor. After administration of magnesium sulfate, the mean (+/- S.E.M.) serum magnesium level rose rapidly from the normal base-line level of 2.0 +/- 0.2 mg per deciliter to 6.1 +/- 0.4 mg per deciliter (0.8 +/- 0.1 to 2.5 +/- 0.2 mmol per liter) (P less than 0.001) at 30 minutes and remained markedly elevated. Concentrations of total and ionized calcium fell gradually in all subjects from normal base-line concentrations, 8.6 +/- 0.2 and 4.4 +/- 0.1 mg per deciliter (2.2 +/- 0.1 and 1.1 +/- 0.03 mmol per liter), respectively, into the hypocalcemic range, reaching a nadir of 7.6 +/- 0.2 and 3.9 +/- 0.1 mg per deciliter (1.9 +/- 0.1 and 0.98 +/- 0.03 mmol per liter), respectively, at three hours (P less than 0.001). Parathyroid hormone levels fell rapidly in response to magnesium infusion, from 13.1 +/- 2.5 to 7.8 +/- 0.7 pg per milliliter at 30 minutes, and were significantly below base-line levels for two hours despite frank hypocalcemia. These results suggest that hypermagnesemia rapidly decreases the secretion of parathyroid hormone in vivo in human subjects and that parathyroid hormone levels remain depressed despite concomitant hypocalcemia. The results also suggest that the hypocalcemia associated with hypermagnesemia may be due in part to the suppressive effects of hypermagnesemia on parathyroid hormone secretion.