Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks' gestation in pregnancies ending in preterm delivery.

OBJECTIVE: This study tested the hypothesis that maternal stress is associated with elevated maternal levels of corticotropin releasing hormone and activation of the placental-adrenal axis before preterm birth. STUDY DESIGN: In a behavior in pregnancy study, 524 ethnically and socioeconomically diverse women were followed up prospectively and evaluated at 3 gestational ages: 18 to 20 weeks, 28 to 30 weeks, and 35 to 36 weeks. Maternal variables included demographic data, medical conditions, perceived stress level, and state anxiety. Maternal plasma samples were collected at each gestational age. Eighteen case patients with spontaneous onset of preterm labor were matched against 18 control subjects who were delivered at term, and their samples were assayed for corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol by means of radioimmunoassay. Statistical tests were used to examine mean differences in these hormones. In addition, the relationship between stress level and each hormone was tested with a Pearson correlation coefficient and hierarchic multiple regressions in each group. RESULTS: Patients who had preterm delivery had significantly higher plasma corticotropin-releasing hormone levels than did control subjects at all 3 gestational ages (P <.0001). Analyses did not find any differences in reported levels of stress between 18 to 20 weeks' gestation and 28 to 30 weeks' gestation. A hierarchic multiple regression indicated that maternal stress level at 18 to 20 weeks' gestation and maternal age accounted for a significant amount of variance in corticotropin-releasing hormone at 28 to 30 weeks' gestation, after controlling for corticotropin-releasing hormone at 18 to 20 weeks' gestation (P <. 001). In addition, patients who were delivered preterm had significantly elevated plasma levels of adrenocorticotropic hormone at all 3 gestational ages (P <.001) and significantly elevated cortisol levels at 18 to 20 weeks' gestation and 28 to 30 weeks' gestation (P <.001). CONCLUSION: Maternal plasma levels of corticotropin-releasing hormone are significantly elevated at as early as 18 to 20 weeks' gestation in women who are subsequently delivered preterm. Changes in corticotropin-releasing hormone between 18 to 20 weeks' gestation and 28 to 30 weeks' gestation are associated with maternal age and stress level at 18 to 20 weeks' gestation. Maternal stress and corticotropin-releasing hormone levels may be potential markers for the patient at risk for preterm birth. Activation of the placental maternal pituitary-adrenal axis is consistent with the classic endocrine response to stress.

Corticotrophin-releasing hormone and CRH-binding protein. Differences between patients at risk for preterm birth and hypertension.

BACKGROUND: During pregnancy in the second and third trimester there is a progressive rise in plasma CRH thought to be secreted by the placenta. Plasma CRH-BP inactivates CRH, which may prevent its peripheral action on the maternal pituitary and myometrium. In the last few weeks of pregnancy CRH-BP decreases, thereby causing an increase in free CRH or a CRH/CRH-BP complex available to play a role in the onset of parturition. OBJECTIVE: We tested the hypothesis that differences in CRH, CRH-BP, or a CRH/CRH-BP complex in patients at risk for preterm birth (PTB) and hypertension (HYP) account for the differences in the timing of parturition. METHODS: From a Behavior in Pregnancy Study database, we identified 18 patients who had spontaneous PTB and 23 patients who developed HYP. Both groups were case controlled and matched with patients who delivered at term (Normal). Maternal plasma samples had been appropriately collected from these patients at 18-20, 28-30, and 35-36 weeks gestational age. CRH levels were measured by double antibody RIA kit and the CRH-BP by a immunoradiometric technique. A CRH-BP/CRH dimer complex index was calculated. Statistical analysis was done using Kruskal-Wallis test for two cases. RESULTS: Maternal CRH (pg/ml) in the PTB cases compared to the HYP cases was significantly elevated at all three time periods. Maternal CRH-BP (pg/ml) in the PTB versus HYP cases was significantly lower at all three time periods in the PTB cases compared to the HYP cases. Maternal CRH-BP/CRH dimer complex index was significantly lower in the PTB cases at all three time periods than either the controls or the HYP cases, suggesting excessive CRH. The mean GA at delivery for the PTB cases was significantly lower than the control or HYP cases. CONCLUSIONS: These results suggest that those patients at risk for PTB have significantly elevated CRH, lower CRH-BP, and a reduced CRH-BP/CRH dimer complex index at all three time periods of assessment.

Long-term nitric oxide blockade in the pregnant rat: effects on blood pressure and plasma levels of endothelin-1.

OBJECTIVE: Abnormalities in the production of nitric oxide and endothelin-1 have been implicated in the development of preeclampsia. We postulated that long-term nitric oxide synthase inhibition with L-nitro-arginine methyl ester would induce sustained hypertension, a rise in plasma levels of endothelin-1, and fetal growth restriction. STUDY DESIGN: Conscious virgin and pregnant Sprague-Dawley rats received infusions of vehicle or L-nitro-arginine methyl ester (2.5 mg/kg/hr) for 11 days. Mean arterial pressure was assessed serially. On day 21 of gestation (or equivalent in virgin rats) plasma was collected for endothelin-1 levels; pup weight and litter size were determined. Data were analyzed with analysis of variance and regression techniques. RESULTS: Mean arterial pressure was constant in virgin control rats (n = 7) but declined in pregnant control rats (n = 11) as gestation advanced. Nitric oxide synthase inhibition in virgin (n = 10) and pregnant (n = 11) rats caused sustained elevations in mean arterial pressure (165 +/- 7 vs 100 +/- 3 mm Hg, L-nitro-arginine methyl ester vs control virgin rats, p < 0.0001; 149 +/- 5 vs 91 +/- 2 mm Hg, L-nitro-arginine methyl ester vs control pregnant rats, p < 0.0001). L-nitro-arginine methyl ester induced a rise in plasma endothelin-1 levels in virgin (4.4 +/- 0.1 vs 3.5 +/- 0.1 pg/ml, L-nitro-arginine methyl ester vs control, p < 0.0001) and pregnant rats (3.0 +/- 0.1 vs 2.6 +/- 0.1 pg/ml, L-nitro-arginine methyl ester vs control, p < 0.0001). Pregnant rats had lower endothelin-1 levels than did virgin rats (p < 0.0001). Mean arterial pressure and endothelin-1 were significantly correlated in pregnant rats. L-nitro-arginine methyl ester decreased pup weight (2.4 +/- 0.4 vs 3.7 +/- 0.2 gm/pup/litter, L-nitro-arginine methyl ester vs control, p < 0.01) and litter size (6.6 +/- 1.3 vs 10.2 +/- 0.9 pups/litter, L-nitro-arginine methyl ester vs control, p < 0.05). CONCLUSIONS: Long-term nitric oxide synthase blockade causes sustained hypertension, elevated levels of endothelin-1, and fetal growth restriction. Although the endocrine and pressor effects are not unique to pregnancy, this model clearly induces some of the changes seen in preeclampsia and may be useful for studying specific interventions.

Adenosine modulates hypoxia-induced atrial natriuretic peptide release in fetal sheep.

The effects of adenosine on atrial natriuretic peptide (ANP) secretion were determined in chronically catheterized fetal sheep (> 0.8 term). Adenosine was infused into the the right jugular vein for 1 h at 8 +/- 0.4 (5 fetuses), 160 +/- 8 (6 fetuses), and 344 +/- 18 micrograms.min-1.kg estimated fetal wt-1. Fetal arterial blood gases and pH were generally unaffected by adenosine, although mean arterial CO2 tension increased transiently by 2-5 Torr and pH fell progressively during the highest rate of infusion. During the intermediate and high infusion rates, fetal hemoglobin concentrations increased by 11-13% and mean fetal heart rate rose by 18% from a control value of approximately 167 beats/min. Mean arterial pressure was not affected during adenosine infusion. Adenosine significantly increased fetal plasma ANP levels, with maximum concentrations 1.80, 2.36, and 2.51 times greater than control means (142-166 pg/ml) for the respective infusion rates of 8, 160, and 344 micrograms.min-1.kg estimated fetal wt-1. In seven fetuses, reducing fetal arterial O2 tension by approximately 9-10 Torr from a control of 23 +/- 1.3 Torr increased plasma ANP concentrations approximately 2.4 times the control mean of 176 pg/min. Adenosine-receptor blockade with 8-(p-sulfophenyl)-theophylline reduced by 50% the maximum hypoxia-induced rise in plasma ANP concentrations. It is concluded that adenosine causes a dose-dependent rise in fetal plasma ANP concentrations and modulates fetal ANP release during hypoxia.

Atrial natriuretic peptide metabolism during pregnancy in the rat.

OBJECTIVE: Our purpose was to determine whether plasma clearance rates and production rates of atrial natriuretic peptide 99-126 are altered during pregnancy in the rat. STUDY DESIGN: Twelve virgin and 12 late-pregnant chronically instrumented, conscious, unrestrained Sprague-Dawley rats were studied. Mean arterial pressure, heart rate, and plasma atrial natriuretic peptide levels were measured before and during a 40-minute continuous infusion of atrial natriuretic peptide (10 ng/kg/min). RESULTS: Control mean arterial pressure was 106 +/- 5 mm Hg in virgin rats versus 97 +/- 4 mm Hg in pregnant rats. Atrial natriuretic peptide infusion did not significantly affect mean arterial pressure in either group of animals but decreased heart rate in virgin rats. Basal plasma atrial natriuretic peptide levels were significantly higher in virgin than in pregnant rats (107 +/- 10 vs 78 +/- 7 pg/ml, respectively, p < 0.05). Atrial natriuretic peptide infusion significantly increased plasma levels in both groups to similar (183 +/- 19 and 154 +/- 14 pg/ml, virgin vs pregnant rats). Calculated plasma clearance rates were similar in virgin and pregnant rats (166 +/- 27 vs 155 +/- 17 ml/kg/min). Estimated production rates of atrial natriuretic peptide were higher in virgin then in pregnant rats (15.1 +/- 1.4 vs 11.4 +/- 1.1 ng/kg/min, p < 0.05). CONCLUSIONS: Plasma atrial natriuretic peptide levels are lower in chronically instrumented near-term pregnant rats compared with levels in virgin rats. This is not related to differences in plasma atrial natriuretic peptide clearance rates but rather to a decrease in production rates in late pregnancy.

Effect of pregnancy on the vasodepressor response to atrial natriuretic factor.

OBJECTIVE: We attempted to determine whether pregnancy alters the vasodepressor response to both physiologic and pharmacologic infusions of atrial natriuretic factor 99-126. STUDY DESIGN: Ten virgin and 10 pregnant (17 +/- 1 days of gestation) conscious, unrestrained Sprague-Dawley rats with chronic indwelling vascular catheters were studied. Mean arterial pressure and heart rate were measured in response to steady-state infusions of either saline solution or increasing concentrations of atrial natriuretic factor (range 5 to 2560 ng.kg-1.min-1). RESULTS: Basal mean arterial pressure was significantly lower in pregnant rats than in virgin rats (89 +/- 3 vs 97 +/- 2 mm Hg, p < 0.02). Atrial natriuretic factor induced significant dose-dependent decreases in mean arterial pressure and heart rate in virgin and pregnant rats (p < 0.001). The hypotensive effects of atrial natriuretic factor were blunted in the pregnant rats only in response to the highest concentrations of atrial natriuretic factor administered (-27 +/- 3 mm Hg in pregnant rats vs -43 +/- 3 mm Hg in virgin rats, p < 0.005). CONCLUSIONS: The vasodepressor response to physiologic infusions of atrial natriuretic factor was not affected by pregnancy status. However, pharmacologic infusions of atrial natriuretic factor resulted in a blunted vasodepressor response in the pregnant animals. This may be due to alterations in vascular atrial natriuretic factor receptors, changes in the clearance rate of atrial natriuretic factor, or the modulating effects of other vasoactive hormones.

Atrial natriuretic factor: the effects of pregnancy and a high-salt diet on atrial levels.

The chronic and relatively acute changes in blood volume that occur during pregnancy and post partum may be associated with alterations in the content of atrial natriuretic factor in the atria. We measured the concentration of atrial natriuretic factor in the right and left atria of virgin, pregnant, and postpartum Sprague-Dawley rats by radioimmunoassay as well as the concentration of atrial natriuretic factor in the atria and plasma of term pregnant rats on a high-salt diet. Neither right nor left atrial concentrations of atrial natriuretic factor were elevated during pregnancy in animals on a normal diet, but both were increased during the first 2 days after delivery. Term pregnant rats on a high-salt diet showed a small increase in atrial natriuretic factor levels in the left atria only, without any change in plasma atrial natriuretic factor levels. We conclude that relatively acute changes in fluid and electrolyte balance are more likely than chronic ones to be associated with alterations in atrial natriuretic factor concentrations in the atria.

Perinatal factors influencing atrial natriuretic peptide levels in umbilical arterial plasma at the time of delivery.

Little is known about atrial natriuretic peptide metabolism or secretion in the human fetus. The purpose of this study was to determine if both the placenta and umbilical vessels are possible sites of atrial natriuretic peptide metabolism and to evaluate the effects that labor, route of delivery, prolonged pregnancy, preeclampsia, and fetal distress have on umbilical arterial atrial natriuretic peptide levels. We found that plasma atrial natriuretic peptide levels in the umbilical artery are significantly greater than those in the vein (p less than 0.001). Umbilical arterial and umbilical venous atrial natriuretic peptide levels were higher in plasma samples collected immediately at delivery when compared with those obtained 10 minutes later (p less than 0.001). Umbilical arterial atrial natriuretic peptide levels were elevated in pregnancies complicated by preeclampsia and fetal distress (p less than 0.01). Labor, route of delivery, and prolonged pregnancy had no effect on umbilical arterial atrial natriuretic peptide levels. We propose that both the placenta and umbilical vessels contain atrial natriuretic peptide receptors that are involved in the clearance or metabolism of atrial natriuretic peptide. The increased umbilical arterial atrial natriuretic peptide levels present in preeclampsia and fetal distress may reflect an attempt by the fetus to regulate blood flow.