Acceleration Of Fetal Lung Maturation Research Articles

588 Perinatal Factors Associated with Multiple Large Cysts on Chest Computed Tomography in Extremely Premature Infants with Chronic Lung Disease

ObjectiveTo identify perinatal factors associated with multiple large cysts on chest computed tomography (CT) in extremely premature infants with chronic lung disease (CLD).MethodsA case-control study of 87 infants with CLD...

The pattern of change in the lecithin/sphingomyelin ratio in patients with preterm premature rupture of membranes between 24 and 34 weeks' gestation.

To report the pattern of change in the lecithin/sphingomyelin (L/S) ratio in patients with preterm premature rupture of membranes (PPROM) between 24 and 34 weeks' gestation. L/S was determined prospectively using transvaginally and transabdominally collected amniotic fluid from patients with PPROM between 24 and 34 weeks' gestation. Samples were collected prospectively on admission and every 48 to 96 hours until L/S was > or =2.0. All patients received intramuscular betamethasone weekly. Fifty-five patients were included in the study. One hundred twenty-seven samples were collected transvaginally and nine were collected transabdominally. Cox regression analysis showed that a higher initial L/S value and more advanced gestational age were associated with accelerated lung maturation. Among patients at > or =29 weeks' gestation with an initial L/S of > or =1.5 and <2.0 (n=17), 15 of 17 (88%) reached L/S > or = 2 at a mean of 3.1 +/- 1.7 days (range 1.0 to 7.0 days). With an initial L/S of > or =1.0 and <1.5 (n=16), 14 of 16 (88%) patients reached L/S > or =2 at a mean of 4.1 +/- 1.9 days (range 1.7 to 7.0 days). With an initial L/S of <1.0 (n=11), 6 of 11 (54%) patients reached L/S > or =2 at a mean of 5.0 +/- 1.6 days (range 4.7 to 6.8 days). Our data document a dramatic acceleration of fetal lung maturation among patients with PPROM at > or = 29 weeks.

Ação da Betametasona em Ratas Prenhes: Impacto sobre os Níveis de Corticosterona e Glândulas Adrenais Maternas e Fetais

Purpose: the repetitive use of antenatal corticosteroid therapy for acceleration of fetal lung maturation has been common in cases at risk of preterm delivery. We studied the corticosterone levels at term and the morphologic aspects in the maternal and fetal adrenal glands submitted to the effect of betamethasone in the second half of rat pregnancy in order to verify its consequences. Methods: thirty female pregnant rats were divided into three groups of ten animals each. Group I received betamethasone on the 11th, 12th, 18th and 19th day of pregnancy. Group II received distilled water on the same days (control group). Group III did not receive any drug (stress control group). All rats were sacrificed on the 20th day of pregnancy when plasma corticosterone levels of dams were assessed and the maternal and fetal adrenal glands were studied by light microscopy. Results: plasma corticosterone level of dams was lower in the group treated with betamethasone (4.8 mg/dL) when compared with the control groups (17.7 and 26.8 mg/dL). The light microscopy study revealed cytoplasmatic vacuolation in the fasciculate zone in the maternal and fetal adrenal glands, which indicates adrenal suppression. Conclusions: the antenatal repetitive and prolonged use of corticosteroids in pregnant rats for acceleration of lung fetal maturation causes maternal and fetal adrenal suppression.

Effect of reactive oxygen species on fetal lung maturation

Objectives: Fetal lung maturation in preterm infants with chorioamnionitis is known to be accelerated. However, the molecular basis of this pathological acceleration has not been elucidated. We investigated whether reactive oxygen species play a role in the acceleration of fetal lung maturation. Study Design: On the 16th day of gestation, xanthine (1 mM) and xanthine oxidase solution (0.1–100 mU/ml) were injected into the intrauterine cavity of pregnant rats. On the 19th day of gestation, we examined the expression of the mRNA of surfactant associated proteins A, B and C (sp-A, sp-B and sp-C) by reverse transcription-polymerase chain reaction. Results: sp-A, sp-B and sp-C mRNAs were observed in lung tissue from fetal rats stimulated by xanthine–xanthine oxidase in contrast to the control. Conclusion: Reactive oxygen species in amniotic fluid might be an important factor in accelerated fetal lung maturation associated with chorioamnionitis in the rat experimental model.

Corticosteroid therapy for prevention of respiratory distress syndrome in severe preeclampsia

Objective: The objective of the study was to determine the efficacy and side effects of corticosteroid therapy for pregnant women with severe preeclampsia in the prevention of respiratory distress syndrome in their premature neonates. Study Design: A prospective double-blind randomized trial enrolled 218 pregnant women with severe preeclampsia and gestational age between 26 and 34 weeks. One hundred ten received betamethasone (12 mg administered intramuscularly, repeated after 24 hours and then once a week) and 108 received placebo. Relative risks and 95% confidence intervals of respiratory distress syndrome and other neonatal and maternal complications were calculated for corticosteroid use. Results: Frequency of respiratory distress syndrome was significantly reduced in the corticosteroid group (23%) with respect to the placebo group (43%), with a relative risk of 0.53 (95% confidence interval 0.35-0.82). Relative risks of intraventricular hemorrhage, patent ductus arteriosus, and perinatal infection were significantly decreased in the corticosteroid group: 0.35 (95% confidence interval 0.15-0.86), 0.27 (95% confidence interval 0.08-0.95), and 0.39 (95% confidence interval 0.39-0.97), respectively. There was no significant difference in the frequency of stillbirth, but the neonatal mortality rate was lower in the corticosteroid group (14%) than in the placebo group (28%), with a relative risk of 0.5 (95% confidence interval 0.28-0.89). There was increased risk of gestational diabetes but of no other maternal complication after corticosteroid therapy, and mean blood pressures were similar in the 2 groups. Conclusions: Antenatal corticosteroid therapy with betamethasone for acceleration of fetal lung maturity is a safe and efficient treatment in patients with severe preeclampsia at between 26 and 34 weeks’ gestation. (Am J Obstet Gynecol 1999;180:1283-8.)

Thyroarytenoid muscle electrical activity during spontaneous apneas in preterm lambs.

Laryngeal dynamics plays a major role during perinatal life, a period of respiratory control immaturity. Continuous electromyographic (EMG) activity of a laryngeal adductor muscle (thyroarytenoid [TA] muscle), was recently observed throughout provoked central apneas, either isolated or during induced periodic breathing, in full-term lambs. The aim of the present study was to test if continuous TA EMG activity was also present during spontaneous apneas in nonsedated preterm lambs. We studied 7 premature lambs (term 131 +/- 1 d of postconceptional age). Premature birth was induced after acceleration of fetal lung maturation. Electrodes for diaphragm, inferior pharyngeal constrictor (IPC), and TA electromyograms, electrocardiogram, electroencephalogram, eye movement, and airflow recordings were implanted. Radiotelemetry recordings were repeated from 135 to 149 +/- 8 d of postconceptional age. A total of 2,088 apneas (2,020 central and 68 mixed) >/= 3 s were recorded in the lambs, including 57 epochs of periodic breathing. Continuous TA EMG activity was present throughout 88.4% of all apneas and 98.4% of apneas during periodic breathing, regardless of the sleep stage. These results suggest that active glottic closure is frequent during spontaneous central apneas in this model of prematurity. This unique model will allow us to study controlling mechanisms and consequences of glottic closure during neonatal apneas.

Der Stellenwert der pränatalen Lungenreifung

Morbidity and mortality of low-weight infants depend mainly on the respiratory-distress syndrome (RDS) and its complications, such as neonatal asphyxia and intraventricular haemorrhage. This underlines the importance of prenatal prevention of RDS. The results of the present multicentre studies demonstrate successful acceleration of fetal lung maturation by glucocorticoids and ambroxol. Both agents lower the RDS-rate two to threefold. The effectiveness in accelerating fetal lung maturation is comparable. In contrast to glucocorticoids, ambroxol seems to have no severe potential maternal or fetal side effects. We believe that prenatal prevention of RDS remains the treatment of choice even if neonatal surfactant therapy is expected to open up new aspects for the future.

Prevention and treatment of fetal lung immaturity.

In the last 10 years the strategy for the prevention of neonatal respiratory distress syndrome (RDS) has been directed towards the acceleration of fetal lung maturity in utero by means of drugs administered to the mother, the most thoroughly investigated being glucocorticoids (GC), and to the development of surfactant substitutes for the treatment of surfactant deficiency at birth or following the development of RDS. GC decreases the incidence of RDS in the neonate delivered between 28 and 32 weeks and weighing less than 1,500 g. The type of GC and the drug-delivery interval are critical. Harmful potential side effects of GC have led to the testing of other drugs capable of accelerating fetal lung maturity, among which are ambroxol and aminophylline. Ambroxol has been shown to significantly reduce RDS compared to placebo without causing important adverse effects in either mother or baby. Our experimental studies on aminophylline have shown that the drug exerts only minor beneficial effects on fetal lung maturation and surfactant production. We have evaluated the association of GC with inositol. The sugar alcohol administered to the mother dramatically affected fetal lung mechanics, reducing GC adverse effects such as the decrease of lung protein content. More recently supplementary surfactant instilled into the trachea has been shown to improve oxygenation of premature babies and to reduce the severity of RDS.

The Biochemistry of Fetal Lung Development

Surfactant therapy for RDS is likely to become widespread in the near future. Animal data indicate that this will not preclude a role for hormonal acceleration of lung maturation. In studies with prematurely delivered and ventilated fetal rabbits, Fiascone et al. have shown that the administration of betamethasone antenatally improves lung compliance, as does intratracheal administration of excess amounts of adult rabbit natural surfactant. If the two therapies are combined, however, an additive effect is observed. This suggests that some of the effects of glucocorticoids on lung compliance are not related to surfactant. Prior glucocorticoid therapy may provide a benefit that differs from that of surfactant therapy because steroids mature the lungs anatomically and enhance nonsurfactant-related tissue compliance. It is also possible that surfactant therapy itself may be more effective in the presence of larger and increased numbers of alveoli. It thus seems likely that in the future both hormonal enhancement of lung maturation and surfactant therapy may be used in combination to further reduce the morbidity and mortality from RDS.

New approaches to hormonal acceleration of fetal lung maturation.

The paper reviews the effects on lung maturation of glucocorticoids in animals and humans and presents relevant recent findings from the author's laboratory. It is now well established that antenatal glucocorticoid treatment reduces the incidence and severity of the respiratory distress syndrome (RDS) in prematurely born infants. The recommended doses of glucocorticoids produce fetal glucocorticoid activity levels similar to those of newborns with RDS or prolonged rupture of the membranes. Extensive follow-up studies have shown that adverse effects on child development are unlikely to occur. It is also evident that a significant number of fetuses do not respond to the treatment, which is of particular consequence in fetuses of less than 28 weeks gestation. These fetuses are less likely to respond to glucocorticoid therapy that fetuses between 28 and 32 weeks gestation and are at a higher risk of developing complications due to their immaturity. In fetal sheep, there is a similar decrease in the efficacy of glucocorticoids on lung maturation with decreasing gestational age. Simultaneous infusion of cortisol, triiodothyronine and prolactin but not of any of these hormones administered singly or in combination of two produced mature lungs in fetal sheep of 125 days gestation. Similar results were obtained with thyrotropin releasing hormone (TRH) and cortisol. It remains to be seen whether the combined administration of glucocorticoids and TRH accelerates lung maturation in human fetuses.

The cellular mechanism of glucocorticoid acceleration of fetal lung maturation. Fibroblast-pneumonocyte factor stimulates choline-phosphate cytidylyltransferase activity.

The cellular mechanism by which glucocorticoids stimulate phosphatidylcholine biosynthesis has been studied in the fetal rat lung in vivo and in cultured fetal rat lung cells of varying levels of complexity. Administration of dexamethasone to pregnant rats at 18 days gestation resulted in a significant increase in saturated phosphatidylcholine content in fetal lung 24 h after injection. Dexamethasone administration increased the activity of fetal lung choline-phosphate cytidylyltransferase by 34%. It had no effect on the activities of fetal lung choline kinase and choline phosphotransferase. Exposure of fetal lung type II cells in organotypic cultures (which contain both type II cells and fibroblasts) to cortisol resulted in a 1.6-fold increase in the incorporation of [Me-3H]choline into saturated phosphatidylcholine. The activities of the enzymes in the choline pathway for the de novo biosynthesis of phosphatidylcholine were not significantly altered except for a 105% increase in choline-phosphate cytidylyltransferase activity. Treatment of monolayer cultures of fetal type II cells with cortisol-conditioned medium from fetal lung fibroblasts resulted in a 1.5-fold increase in saturated phosphatidylcholine production. This effect correlated with a doubling of choline-phosphate cytidylyltransferase activity. Additional evidence that this stimulatory action is mediated by fibroblast-pneumonocyte factor, produced by fetal lung fibroblasts in response to cortisol, was obtained. The factor was partially purified from cortisol-conditioned medium of fetal lung fibroblasts by gel filtration and affinity chromatography. Based on biological activity, a 3000-fold purification was obtained. Stimulation of saturated phosphatidylcholine synthesis in type II cells by fibroblast-pneumonocyte factor was maximal within 60 min of incubation. Pulse-chase experiments indicated that the stimulatory effect was correlated with an increased conversion of choline phosphate into CDP choline. Moreover, the enhanced phosphatidylcholine formation by fetal type II cells in response to fibroblast-pneumonocyte factor was accompanied by decreased levels of cellular choline phosphate. These findings further support the concept that glucocorticoid action on surfactant-associated phosphatidylcholine synthesis occurs ultimately at the level of the alveolar type II cell and involves fibroblast-pneumonocyte factor which stimulates the activity of choline-phosphate cytidylyltransferase.

Effect of betamethasone on pressure-volume relationship of fetal rhesus monkey lung.

We have investigated the acceleration of fetal lung maturity following glucocorticoid administration. Air-filling of saline-filling pressure-volume curves were obtained on fetal rhesus monkey lungs after treatment with betamethasone. With air filling there was a marked increase in the total lung capacity (ml air/g at 40 cmH2O) in the treated animals. By normalizing the curves and plotting volume as a percent maximal volume, we examined the shape of deflation curves, a common functional measure of surfactant activity. We found little difference in the shapes between control and steroid-treated animals. With saline filling there was also a similar increase in the lung capacity. As surface tension has a negligible effect on saline pressure-volume curves, we conclude that the primary functional effect of glucocorticoids on the fetal lung may not be an alteration of surface forces. Rather the glucocorticoids seem to accelerate maturity more by increasing lung compliance through structural changes that allow the lung to contain more air for equivalent transpulmonary pressures or pressure changes. This may occur either by increasing the distensibility of already inflatable alveoli or by recruiting new units.

Effects of betamethasone on phospholipid content, composition and biosynthesis in the fetal rabbit lung

Administration of betamethasone (0.2 mg/kg, intramuscularly) to pregnant rabbits had the following effects on the fetal lung at 26–27 days gestation. It increased the amount of phosphatidylcholine in lung lavage by 70% and almost doubled the phosphatidylcholine/sphingomyelin ratio, it increased the rate of incorporation of choline into phosphatidylcholine in fetal lung slices by up to 90%, it increased the activities of pulmonary cholinephosphate cytidylyltransferase and phosphatidate phosphatase by 50% and it reduced the amount of lung glycogen to 60% of the amount in the controls. Betamethasone had no effect on the activities of pulmonary cholinephosphotransferase or lysolecithin: lysolecithin acyltransferase but it sligthly decreased the activity of choline kinase. Betamethasone administration to the doe did not increase the amount of surfactant phospholipid in fetal lung lavage to as great an extent as did direct administration of cortisol to the fetuses. Neither did betamethasone stimulate the activity of pulmonary cholinephosphotransferase. These data suggest that agents other than glucocorticoids mediate the stress-induced acceleration of fetal lung maturation and surfactant production.

Fetal lung maturity in differen abnormal pregnancies (author's transl)

The influence of pathological situations to fetal lung maturation during the last 9 weeks of pregnancy was studied. Lung maturity was determined by four different methods, analyzing the concentration of surfactant in amniotic fluid L/S ratio was measured planimetrically and densitometrically, foam test and surface tension of the liquor amnii were used on this purpose. 89 normal pregnancies for obtaining normal values served as a basis for comparison with pathological events. A general retardation of fetal lung maturity showed 26 patients with rhesus isoimmunization so as 26 patients with diabetes classes A, B and C (White). In three pregnancies complicated by diabetes class D a remarkable acceleration of fetal lung maturity was obvious. 30 patients with placental insufficiency sui generis presented a very inhomogenous development of the fetal lung, whereas in 35 patients with EPH-gestosis a minute acceleration between 33th and 37th week of gestation was found. A good correlation between all of the used methods for measuring the concentration of surfactant was noted. Best reliability in correct prediction of lung maturity showed the method of measuring the surface-tension of the amniotic fluid.

Use of prenatal glucocorticoid therapy to prevent respiratory distress syndrome. A supporting view.

In spite of recent major advances in the care of infants with neonatal respiratory distress syndrome (RDS), this disease continues to extract a great economic and emotional cost. Infants with RDS require sophisticated care for long periods of time, experience substantial morbidity, and may have long term sequelae from the disease or its therapy. However, it now appears that the incidence of RDS can be appreciably lowered by the use of prenatal glucocorticoid therapy in appropriate circumstances. In this commentary, we will review the history, effectiveness, safety, and probable mechanism of glucocorticoids in the acceleration of fetal lung maturation. Glucocorticoid Effects in Animals In 1969, Liggins1noted that a lamb born prematurely at 123 days (term is 150 days) after infusion of glucocorticoids was unexpectedly viable; it was postulated that corticosteroid treatment was inducing lung maturation and causing the appearance of surface active material (SAM) in alveolar spaces. Subsequent

Acceleration of Fetal Lung Maturation by Aminophyllin in Pregnant Rabbits

Acceleration of Fetal Lung Maturation by Aminophyllin in Pregnant Rabbits

Acceleration of fetal lung maturation by aminophyllin in pregnant rabbits.

To test the hypothesis that fetal lung maturation can be accelerated by one of the xanthine derivatives, aminophyllin was given to 40 pregnant rabbits beginning on the 20th gestational day for a period of 7-10 days. The fetuses were delivered by cesarean section and fetal lung maturity was assessed by determining the biochemical, functional, and ultrastructural characteristics of aminophyllin-treated vs. control animals. The phospholipid content of the lung tissue homogenate from the aminophyllin-treated group was significantly higher than in the control subjects (saline injected) at 28 days of gestation (421 +/- 9 vs. 368 +/- 12 mug/mg wet wt, mean +/- SEM) and at 29 days of gestation (531 +/- 10 vs. 475 +/- 20). The alveolar wash phospholipid content of the aminophyllin-treated group was higher at 30 days (167 +/- 9 mug/mg dry wt, mean +/- SEM vs. 117 +/- 17). The lung compliance derived from pressure volume curves was also significantly higher in the aminophyllin-treated group when compared with controls at 27 days of gestation (0.023 +/- 0.0005 ml/cm H2O, mean +/- SEM vs 0.010 +/- 0.0002) and at 28 days of gestation (0.048 +/- 0.0003 vs 0.035 +/- 0.0006). There was no significant difference in the number of lamellar bodies in the type II cells between the aminophyllin-treated and the control groups. The data show that aminophyllin has accelerating effects on fetal lung maturation in rabbits when the drug is given to pregnant rabbits during the last 7-10 days of gestation.

A comparison of two glucocorticoid regimens for acceleration of fetal lung maturation in premature labor

This study compares fetal corticoid response from conventional dose (12.0 mg.) intramuscular betamethasone to large dose (1,000 mg.) intravenous cortisol administered to women in premature labor for acceleration of fetal lung maturity. To compare these two regimens, 14 women selected at random were treated in groups of seven with either cortisol or betamethasone. Peripheral levels of unconjugated estriol were measured by specific radioimmunoassay prior to the corticoid dose and at 1, 4, 8, and 12 hours following the dose. The rate of corticoid delivery to the fetal hypothalamic-adrenal axis was estimated by the per cent suppression of unconjugated estriol at each post-treatment interval. Least-squares regression lines fitted (P < 0.01) for each regimen were compared for time saved (Δt) when cortisol was used. Mean Δt (1, 4, 8, and 12 hours) was 9.0 ± 0.2 S.E.M. hours. It is concluded that: (1) Intravenous cortisol delivers a fetal corticoid effect that is significantly more rapid in onset and more profound in magnitude than does intramuscular betamethasone and that (2) the cortisol regimen is probably better suited to the acceleration of fetal lung maturation in premature labor when time is short and rapid action is essential.

Acceleration of fetal lung maturation following prolonged rupture of the membranes

Prolonged rupture of the membranes exerts an accelerating effect on fetal lung maturation independent of gestational age or birth weight and resulting in absence of the respiratory distress syndrome (RDS). Sixty-four true-premature infants born of mothers with no complications of pregnancy other than prolonged rupture of the membranes were evaluated for the presence of RDS. In 42 of these infants, membranes were ruptured 24 hours or less prior to delivery, and RDS occurred in 64 per cent. In 22 infants with membranes ruptured more than 24 hours prior to delivery, 31 per cent developed RDS. Lecithin/sphingomyelin ratios showed marked acceleration following membrane rupture, irrespective of gestational age.