Effect of maternal administration of thyrotropin releasing hormone on the preterm fetal pituitary-thyroid axis

We evaluated the response of preterm fetuses to maternal intravenous injection of 400 micrograms of thyrotropin releasing hormone (TRH) between 30 minutes and 5 hours before delivery (n = 12). An additional seven mothers received saline solution and served as control subjects. There were no statistically significant differences in gestational age, birth weight, or Apgar scores between groups. At delivery, concentrations of maternal thyrotropin were elevated in the TRH group compared with the control group (12.0 +/- 1.6 vs 5.6 +/- 0.5 mU/L; p less than 0.005); however, maternal triiodothyronine (T3) values remained unchanged. Significant elevations of fetal thyrotropin and T3 were observed after maternal administration of TRH compared with control subjects (45.8 +/- 7.7 vs 8.4 +/- 0.9 mU/L (p less than 0.002) and 1.3 +/- 0.07 vs 0.7 +/- 0.04 nmol/L or 87 +/- 5 vs 49 +/- 3 ng/dl (p less than 0.001), respectively). Fetal thyroxine (T4) and prolactin values were also elevated after exposure to TRH (135 +/- 5 vs 86 +/- 10 nmol/L or 10.5 +/- 0.4 vs 6.7 +/- 0.8 micrograms/dl (p less than 0.001) and 212 +/- 31 vs 105 +/- 28 micrograms/L (p less than 0.05), respectively). Two hours after birth, a significant increase in T3 but not T4 levels was observed in both groups of infants. These data indicate that fetal exposure to a single dose of TRH via maternal administration of this hormone results in marked stimulation of the preterm fetal pituitary-thyroid axis, as in the fetus at term, and that this treatment does not inhibit the early postnatal surge of T3.     

Response of the maternal, fetal, and neonatal pituitary-thyroid axis to thyrotropin-releasing hormone

Thyrotropin releasing hormone (TRH) readily crosses the placenta and stimulates the fetal pituitary. We studied the response of the maternal and fetal pituitary-thyroid axes to TRH and the influence of prenatal exposure to TRH on the physiological postnatal increase in thyrotropin (TSH) and triiodothyronine (T3) in the neonate. Twenty-six pregnant women received TRH (400 or 600 micrograms) intravenous or saline (controls) either 2 or 12 h before elective cesarean section at term. Administration of 400 micrograms of TRH resulted in significant elevations of maternal TSH (15.7 +/- 2.9 versus 3.2 +/- 0.4 microU/ml, p less than 0.01) and prolactin (416 +/- 94 versus 223 +/- 41 ng/ml, p less than 0.05) 2 h later. Maternal T3 remained unchanged. A higher dose of TRH (600 micrograms) produced comparable results. Maternal administration of TRH (400 micrograms) 2 h before delivery resulted in significant increases in fetal TSH and T3 over controls (21.1 +/- 3.7 versus 4.8 +/- 1.0 microU/ml, and 132 +/- 12 versus 64 +/- 9 ng/dl, p less than 0.01, respectively). Cord blood hormone levels 12 hours after TRH administration were similar to controls. Higher doses of TRH did not produce further increases in fetal TSH or T3. Control and treated neonates demonstrated similar physiological postnatal increases in TSH and T3, suggesting that prior exposure to TRH did not blunt this response. These data suggest that maternal administration of TRH is an effective way of increasing fetal T3 levels, and that this treatment does not inhibit the postnatal surge in TSH and T3.     

Effect of maternal vitamin-A administration on fetal lung vitamin-A stores in the perinatal rat

Vitamin A (retinol) is essential for normal differentiation and integrity of developing respiratory epithelium and its deficiency has been linked to an increased susceptibility to lung injury. Because significant vitamin-A storage occurs in the fetal lung near term in the perinatal rat, prematurely born animals deprived of adequate stores in their lungs may be susceptible to the adverse effects of vitamin-A deficiency. It would be desirable if lung vitamin-A stores could be augmented with maternal administration, but the feasibility of this strategy has not been reported. We therefore conducted this study in rats to determine whether maternal administration of vitamin A could increase the lung stores of vitamin A in the offspring. Vitamin-A-sufficient pregnant rats were given a single dose of either vitamin A (50,000 IU retinyl palmitate) or 0.9% saline solution on gestational day 16 (term = 21 days) by the intragastric route. High-performance liquid chromatography was used to measure concentrations of vitamin A and its esters in fetal and neonatal lungs and livers at times ranging from gestational day 17 through 21, and from postnatal day 1 through 14. The concentrations of vitamin-A esters in the lungs of fetuses and newborn pups of the vitamin-A-treated animals were significantly (1.7- to 7.1-fold) higher than those of the control group. This increase in the lung vitamin-A ester concentrations was seen within 24 h of maternal administration and persisted throughout the 14-day postnatal period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hydrocortisone on the metabolism of phosphatidylcholine in maternal and fetal rabbit lungs and livers

Administration of hydrocortisone to pregnant rabbits caused a decrease in weights of fetal body and lung and an increase in the incorporation of choline into fetal lung PC. The authors found no induction of the enzymes related to the incorporation of choline into PC in fetal lung. Also, there was no stimulation of any enzymatic activity of CDP-choline pathway or PC-lysoPC cycle pathway in maternal lung and liver or fetal liver. In addition to the acceleration of choline incorporation into fetal lung PC by the cortisol, hydrocortisone also significantly stimulated the secretion of lung PC affected by glucocorticoids may also be related to apparent fetal lung maturation.     

Effect of antenatal administration of thyrotrophin releasing hormone on fetal flow velocity waveforms

AIM—To determine whether antenatal administration of thyrotrophin releasing hormone (TRH), to promote lung maturation, alters blood flow through the fetal middle cerebral, umbilical artery, or ductus arteriosus and through the maternal uterine arteries.METHODS—The effect of transplacentally administered TRH on the fetal circulation was prospectively evaluated in 30 patients between 24 and 34 weeks'' gestation. TRH (400 µg) was given to the mother intravenously either as a bolus or an infusion. Fetal effects were determined by measuring the maximum velocity and pulsatility index (PI) in middle cerebral artery, ductus arteriosus, uterine artery and umbilical artery Doppler waveforms. Measurements were made immediately before, and 10 and 60 minutes after maternal TRH administration.RESULTS—Intravenous injection of TRH had no significant effect on PI in the uterine, umbilical, or middle cerebral artery and the ductus arteriosus within 60 minutes of administration in either group.CONCLUSION—The antenatal use of TRH in conjunction with steroids for fetal lung maturity does not affect utero-placental or fetal haemodynamic variables, as measured by Doppler. These findings, therefore, do not support the suggestion that antenatal intravenous administration of TRH either as bolus or infusion may have immediate adverse vascular effects in the fetus.     

Transplacental stimulation of fetal lung maturation: effect of triiodothyronine in the female and male rabbit fetus

We have recently demonstrated that intramuscular administration of triiodothyronine (T3) or thyroxine (T4) to the rabbit doe results in its transfer across the placenta. In this study we investigated the effect of maternally administered T3 upon the functional and morphologic fetal lung maturation. T3 (175 micrograms/kg) or the vehicle was injected intramuscularly into the New Zealand White rabbit does on days 25 and 26 of gestation. On day 27 of pregnancy, the does were killed and the fetuses were delivered. Maternal and fetal plasma T3, glucose and insulin and fetal plasma corticosteroid concentrations were determined. The functional pulmonary maturity was assessed by performing the pressure-volume hysteresis while morphologic maturity was established by histologic techniques. Enhanced functional as well as morphologic fetal lung maturation was observed in female as well as male fetuses in T3-treated animals. However, there was a significant increase in the fetal mortality after T3 treatment, and the duration of survival in the extrauterine environment on premature delivery was not prolonged.     

Effect of exogenous surfactant on the development of surfactant synthesis in premature rabbit lung

Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full recovery from respiratory distress syndrome requires development of endogenous surfactant synthesis and metabolism. The influence of exogenous surfactant on the development of surfactant synthesis in premature lungs is not known. We hypothesized that different exogenous surfactants have different effects on the development of endogenous surfactant production in the premature lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg body weight of natural rabbit surfactant, Survanta, and Exosurf and measured their effects on the development of surfactant synthesis. Additional experiments tested how these surfactants and Curosurf affected surfactant protein (SP) SP-A, SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the incorporation of 3H-choline and 14C-glycerol into disaturated phosphatidylcholine recovered from lamellar bodies. Randomized-block ANOVA showed significant differences among treatments for incorporation of both labels (p < 0.01), with natural rabbit surfactant less than control, Survanta greater than control, and Exosurf unchanged. Additional experiments with natural rabbit surfactant alone showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated disaturated phosphatidylcholine synthesis (173 +/- 41% of control; p = 0.01), increased total lamellar body disaturated phosphatidylcholine by 22% (p < 0.05), and increased 14C-disat-PC specific activity by 35% (p < 0.05). The response to Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant release. No surfactant altered the expression of mRNA for SP-A, SP-B, or SP-C. We conclude that surfactant replacement therapy can enhance the maturation of surfactant synthesis, but this potential benefit differs with different surfactant preparations.     

Effect of premature delivery on the maturation of the Hering-Breuer inspiratory inhibitory reflex in human infants.

The Hering-Breuer inspiratory inhibitory reflex was studied serially in a group of premature infants and in a group of term infants in the immediate postnatal period. The premature infants had a stronger inspiratory inhibitory reflex than did the term infants at birth; this reflex decreased with maturation of the premature. Development in the extrauterine environment significantly delayed the rate of disappearance of this reflex. This may indicate that premature delivery retards the neurologic maturation of the human infant. The term infant showed no change in the activity of the inspiratory inhibitory reflex in the first five days of life.     

Effect of supplementary surfactant on in vivo lung mechanics in the premature rabbit neonate

Premature newborn rabbits, delivered on day 27 of gestation, were subjected to positive-pressure ventilation, with or without treatment with natural surfactant. The surfactant, obtained by centrifugation of lung wash from adult rabbits, was deposited in the tracheal cannula before the onset of ventilation. Parameters of lung mechanics, recorded during spontaneous ventilation after 1 h, were significantly improved in animals receiving surfactant. In comparison with littermate controls, surfactant-treated animals also had less prominent bronchiolar epithelial lesions. We conclude that treatment with supplementary surfactant facilitates functional adaptation of the premature lung and prevents the development of epithelial lung lesions during artificial ventilation.This work was supported by The Swedish Medical Research Council (Project No. 3351), The Swedish National Association against Heart and Chest Diseases, and Karolinska Institutets fonder     

Effect of premature delivery on rat lung retinol (vitamin A) and retinyl ester stores

Low plasma retinol (vitamin A) in premature infants has been associated with bronchopulmonary dysplasia. Also, retinol (vitamin A) deficiency is characterized by loss of cilia and squamous metaplasia of the respiratory tract, similar to the histological lesions of bronchopulmonary dysplasia of the premature infant. Recent work showed that the fetal rat lung retinyl palmitate stores were high preterm, but fell abruptly between 21 days of gestation and postpartum. This report extends this observation by showing that lung retinyl palmitate also decreases after cesarean section delivery preterm. Lung retinol and retinyl palmitate in the lungs of 21-day gestation fetuses delivered by cesarean section and stimulated to breath were compared to their in utero littermates. In utero lungs contained 2.2 +/- 0.14 micrograms/g dry weight retinol and 14.9 +/- 0.8 micrograms/g dry weight retinyl palmitate. Lungs from littermates that had been removed from the uterus and breathed on their own for 4 h had lower retinol (1.6 +/- 0.08 micrograms/g) and retinyl palmitate (11.3 +/- 0.4 micrograms/g; p less than 0.01). Fetal lung contains retinyl palmitate stores that are readily mobilized with delivery at term or preterm.     

Influence of maternal birth weight on rate of fetal growth and duration of gestation

Birth certificates of infants born in Tennessee during 1979 to 1984 were linked with the birth certificates of their mothers, who were born in Tennessee during 1959 to 1966 (n = 43,891) to study the association between maternal and infant birth weights. A highly significant association (P less than 0.0001) between maternal and infant birth weights was found for both blacks and whites. Women who weighed 4000 to 4499 g at birth were at lowest risk for delivery of a small for gestational age (SGA) infant (5.9% for whites, 4.8% for blacks). The risk of giving birth to an SGA infant increased with decreasing maternal birth weight, reaching a maximum of 19.8% for white mothers who weighed 2000 to 2499 g at birth, and 20.0% for black mothers who weighed 1000 to 1499 g at birth. In contrast, the rate of preterm birth varied much less by maternal birth weight for both whites and blacks. These data suggest that maternal birth weight exerts a stronger influence on intrauterine growth than on the duration of gestation. Women who were smaller than average at birth should be considered at high risk for delivery of an SGA infant.     

Effect of aminophylline on the synthesis of dipalmitoyl phosphatidyl choline in fetal rabbit lung

Aminophylline (A) administration to pregnant rabbits resulted in accelerated formation of phospholipids, the known important components of pulmonary surfactant [1]. The present study was undertaken to determine the effect of A on one of the pathways involved in the incorporation of palmitic acid into phosphatidyl choline (PC)--the "deacylation-reacylation pathway." A was injected intraperitoneally into rabbit fetuses at 27 days of gestation and its effect on palmitoyl CoA synthetase (PCS) and lysopalmitoyl choline acyl transferase (LPC-AT) were studied. Only LPC-AT was enhanced significantly (P less than 0.05) as a result of direct administration of A. This study supports the suggestions by previous investigators that antenatal administration of aminophylline may prove to be an effective means of enhancing lung maturation by stimulating the formation of pulmonary surfactant production before premature delivery. However, the dose that was used in this experimental study was far more than the usual clinical dose that had been suggested previously.     

Effect of maternal fluoxetine administration on uterine blood flow, fetal blood gas status, and growth

Clinical depression, diagnosed in 5-15% of women during pregnancy, increases the risk of negative pregnancy outcomes including an increased incidence of low birth weight newborns and preterm delivery. Fluoxetine, a selective serotonin reuptake inhibitor, is often prescribed to treat depression due to its efficacy, high margin of safety, and mild side effects. However, fluoxetine initially increases plasma serotonin concentration, and serotonin causes uterine vasoconstriction in sheep, which could result in fetal hypoxemia. To assess fetal fluoxetine effects, late-gestation pregnant sheep were surgically prepared for the measurement of blood gases, heart rate, blood pressure, and uterine artery blood flow (n = 29). Ewes received a 70-mg bolus i.v. infusion of fluoxetine over 2 min in 10 mL of sterile water followed by continuous infusion at a rate of 100 microg/min for 8 d (n = 14), or continuous infusion of sterile water (n = 15). Transient decreases in uterine artery blood flow, fetal PO(2), and oxygen saturation were observed within the first 15 min after fluoxetine exposure, which did not return to normal values by 24 h. Fetal pH decreased and PCO(2) increased over the first 4 h with a return to normal by 24 h. However, there were no differences in uterine artery blood flow, blood gas status, or cardiovascular measures between the control and fluoxetine group over the rest of the 8-d infusion period. Thus, fluoxetine exposure during pregnancy has transient effects on fetal status that may be of developmental consequence if they occur repetitively.     

Effects of maternal bilateral adrenalectomy and betamethasone administration on fetal rat encephalic development

The present study examined the effects of maternal bilateral adrenalectomy and betamethasone treatment on fetal encephalic development, in terms of fetal body weight, brain weight, DNA, protein and lipid content and morphological development. Both influenced the developmental time patterns of fetal brain and cerebellum. Fetuses of adrenalectomized rats had decreased body weights, whereas brain weight was not affected. Maternal adrenalectomy produces in fetal brain a decreased number of cells and increased cell size, while betamethasone treatment of adrenalectomized rats increased cell number, which was not different from control values; cell size remained lower than in control fetuses. Lipid content was increased in the fetuses of betamethasone-treated rats. In terms of morphological development, laminated structures (hippocampus and brain and cerebellar cortex) were the ones most affected.     

The central effects of thyrotropin-releasing hormone on the breathing movements and electrocortical activity of the fetal sheep

The fetal respiratory and electrocortical effects of thyrotropin-releasing hormone (TRH) administered into the lateral cerebral ventricles, have been investigated in chronically catheterized unanesthetized fetal sheep at 125-140 days of gestation. Stimulatory effects on fetal breathing movements were seen at doses as low as a lug bolus. TRH given as a 5-micrograms bolus followed by a 10 micrograms/h infusion for 2 h induced a rapid switch to significantly faster, deeper, and continuous fetal breathing movements, while the electrocorticogram remained episodic. Fetal breathing movements did not stop during hypoxia. TRH given as a 2-micrograms bolus followed by a 4 micrograms/h infusion or as a 5-micrograms bolus followed by a 5 micrograms/h infusion induced the same stimulation of FBMs, but breathing essentially remained episodic, state related and inhibited by hypoxia. As hypothermia presumably induces a surge in TRH secretion at birth it is possible that TRH has some role in the switch from fetal to postnatal breathing patterns.     

The effect of hypoxia on neurohypophyseal hormone release in fetal and maternal sheep

The effect of hypoxemia on arginine vasopressin (AVP) and oxytocin (OT) release was investigated in the chronically catheterized fetus and ewe. During 30 min of 10% maternal oxygen delivery, mean (+/- SEM) arterial PO2 decreased from 105 +/- 10.6 to 48 +/- 3.5 mm Hg in the ewe and from 21 +/- 1.3 to 12 +/- 0.8 mm Hg in the fetus (each P less than 0.001). Arterial PCO2 decreased from 35 +/- 4.4 to 29 +/- 1.0 mm Hg in the ewe, whereas fetal PCO2 decreased from 43 +/- 2.3 to 35 +/- 3.5 mm Hg (P less than 0.05). Blood pH increased from 7.44 +/- 0.03 to 7.56 +/- 0.04 in the ewe (P less than 0.01) and from 7.36 +/- 0.004 to 7.40 +/- 0.006 in the fetuses (P less than 0.01). Baseline mean AVP levels were identical in ewes and fetuses (0.7 +/- 0.1 microU/ml). After 30 min of hypoxia, plasma AVP levels remained unchanged in the ewes (0.9 +/- 0.1), but increased dramatically in the fetuses (47 +/- 21 microU/ml) (P less than 0.001). There was a highly significant correlation between the duration of hypoxia and log fetal AVP concentrations (r = 0.85). The log fetal plasma AVP also was inversely correlated to the log fetal PO2 values (r = 0.83). Mean baseline fetal and maternal plasma OT levels were 2.6 +/- 0.5 microU/ml and 2.2 +/- 0.5 microU/ml, respectively. After 30 min of hypoxia fetal and maternal OT values were 2.9 +/- 0.8 microU/ml (not significant).     

Effect of maternal NG-nitro-l-arginine administration on fetal growth and hypoxia-induced changes in newborn rats

BACKGROUND: Nitric oxide (NO) inhibition with NG-nitro-l-arginine methyl ester (l-NAME) in the last trimester of pregnancy caused intrauterine growth retardation and hind-limb disruptions in rats. In the present study, the effect of maternal NO inhibition with NG-nitro-l-arginine (l-NNA) on hypoxic newborn rats was investigated. METHODS: Timed-pregnant rats were obtained on gestational day 17. Four groups of rats were used: control, hypoxic, l-NNA and l-NNA + hypoxic groups. In the last two groups, l-NNA (2 mg/kg bolus, i.p.) was administered to the mothers of pups antenatally on 3 consecutive days. Hypoxia was induced in newborn rats by breathing of a mixture of 8% oxygen and 92% nitrogen for 3 h. Pups were then allowed to inhale normal atmospheric air for 30 min. All newborn rats were decapitated on the first day of life after hypoxia and reoxygenation. Brain, heart, lung, liver, kidney and intestinal tissues were studied biochemically. Hypoxia-induced biochemical changes were determined by measuring lipid peroxidation. Histopathologic examination of lung tissue was performed. RESULTS: Nitric oxide synthase inhibition in pregnancy did not cause fetal growth retardation. Hypoxia increased lipid peroxidation in all tissues except the heart; this increase was decreased by maternal l-NNA administration in brain, lung, liver and kidney tissues. However, lipid peroxidation was increased by NO synthase inhibition in the intestines. In the lungs, pulmonary hemorrhage was observed in the hypoxic group. Minimal pulmonary hemorrhage was detected in the l-NNA and l-NNA + hypoxic groups. CONCLUSIONS: These data suggest that antenatal administration of an NO synthase inhibitor acts as both a destructive and protective agent in hypoxic newborn rats.     

内毒素致胎鼠脑白质损伤后Bcl-2和Bax蛋白表达的研究

目的 探讨内毒素致胎鼠脑白质损伤后凋亡蛋白Bcl-2、Bax的表达及其意义.方法 孕鼠随机分为两组:感染组和对照组.感染组:建立宫内感染的动物模型,孕鼠怀孕15 d腹腔注射内毒素;对照组:孕鼠怀孕15 d腹腔注射生理盐水.分别于给药后2、4、12、24、72 h剖腹取胎鼠,取脑组织行组织病理学检查,观察胎盘及胎鼠脑组织病理特点,用免疫组织化学方法检测胎鼠脑组织凋亡蛋白Bcl-2、Bax的表达.结果 感染组胎盘组织见中性粒细胞浸润,胎鼠脑组织病理改变包括脑白质染色减淡,结构疏松等.感染组胎鼠脑组织凋亡蛋白Bcl-2的表达自2 h开始逐渐下降,而Bax的表达自2 h逐渐升高,均于12h达到峰值.2h感染组Bcl-2、Bax的阳性细胞百分数与对照组相比,差异无显著性(P>0.05);而4 h、12 h、24 h和72 h感染组与对照组相比,差异有非常显著性(P<0.01).感染组Bax与Bcl-2的比值均明显高于对照组,在各观察时间点两组相比,差异有非常显著性(P<0.01).结论 内毒素诱导是制备胎鼠脑白质损伤的一种有效形式.在胎鼠脑白质损伤中Bcl-2可能抑制细胞凋亡,Bax可能诱发细胞凋亡,两者的比率变化可能对脑白质损伤后细胞凋亡的调节起重要作用.