Antenatal Glucocorticoid Treatment Research Articles

Antecedents of clinically significant pulmonary hemorrhage among newborn infants.

To evaluate risk factor profiles associated with clinically significant pulmonary hemorrhage (PH) in preterm (PT) and term infants. Case-control study of all infants with PH cared for in three Harvard-affiliated neonatal intensive care units between 1987 and 1994. A total of 50 cases of PH occurred in PT infants (gestational age (GA) of < or = 34 weeks), and 26 cases occurred in near-term/full-term (NT/FT) infants (GA of > 34 weeks). The median age at the time of PH was 46 hours among PT infants compared with 6 hours among NT/FT infants. For PT infants, four factors best predicted PH: a GA of between 24 and 26 weeks and antenatal glucocorticoid treatment reduced the risk (odds ratios (ORs) of 0.7 and 0.3, respectively), whereas requirement for resuscitation with positive pressure ventilation and thrombocytopenia were associated with increased risk (ORs of 4.3 and 4.0, respectively). Among the NT/FT infants, the model included three variables: meconium aspiration (OR 4.9), requirement for resuscitation with positive pressure ventilation (OR 2.9), and hypotension (OR 3.5). Antecedent factors and timing of PH differ between PT and NT/FT infants, suggesting that the mechanisms contributing to PH are influenced by developmental maturity as well as perinatal and neonatal medical conditions and interventions.

Multiple courses of antenatal glucocorticoid treatment and fetal outcome.

Thanks to the US National Institutes of Health Consensus Conference, the odds of antenatal use of glucocorticoids for preventing severe neonatal complications of premature delivery have significantly increased these last years. The belief that neonatal benefits last up to 7 days after the first course and administration of further courses is safe has led many obstetricians to prescribe multiple antenatal glucocorticoid courses. Whether multiple courses offer an advantage over a single course has not been demonstrated. In contrast, there are accumulating evidence suggesting that this practice may have short and long-term side effects. The potential benefits and side effects of multiple antenatal courses of glucocorticoids, extrapolated from experimental data and observational studies, are detailed in this review. Until the results of ongoing randomized trials with long term follow-up are available, the practice of giving multiple courses of glucocorticoids to women should be considered with the greatest caution.

Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood.

During the course of human pregnancy, glucocorticoid (GC) treatment is given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, in animal studies, a number of side effects of perinatal GC treatment have been described. The aim of the present study was to evaluate in humans the effects of antenatal GC treatment on development of the immune system. In addition, we examined the development of immune reactivity in infants born preterm and at term who did not receive GC treatment antenatally. We tested mitogen-induced T cell proliferation, natural killer cell activity, and lipopolysaccharide-induced IL-6 production in cord blood samples. We found that there is a significant effect of gestational age on the capacity of T cells to proliferate and of natural killer cells to kill K562 tumor cells. The capacity to produce IL-6 does not change between gestational age 26 and 41 wk. Moreover, our results show that antenatal treatment with GC does have immunomodulatory effects: T cell proliferation is decreased in infants born very preterm (gestational age 26-31 wk) as well as in infants born between 32 and 36 wk of gestation. In contrast, the activity of natural killer cells is only increased in GC-treated infants born between 26 and 31 wk. We did not observe a significant effect of antenatal GC treatment on the capacity to produce IL-6.

Repetitive Antenatal Glucocorticoid Exposure Matures Preterm Newborn Lamb Renal Responses to Phenylephrine-induced Increases in Blood Pressure 250

Fluid and electrolyte homeostasis in preterm newborns is compromised due to immature renal function. A single antenatal glucocorticoid treatment augments preterm newborn kidney adaptive responses. To assess the effect of multiple betamethasone (BETA) exposures on kidney adaptation (glomerular autoregulation), pregnant ewes were randomized to receive 1 dose of 0.5 mg/kg BETA at 104d gestation (ONE), 3 doses of BETA at 104, 111, and 118 d gestation(MULT) or saline (control; CON). Lambs were delivered at 125 d (Preterm) or 145 d (Term). Two hours following delivery, Preterm mean arterial pressure(MAP), urine flow (Uflow) and glomerular filtration rate (GFR) did not differ among the groups. Phenylephrine infusion (0.4-26μg/kg/min; over 14 min) increased [mean±SEM (p<0.05)] Preterm MAP (41±3 to 53±4mmHg), GFR (0.59±0.12 to 1.59±0.13 ml/min/kg) and Uflow (0.05±0.03 to 0.16±0.04 ml/min/kg) in the MULT group. While MAP also increased in the ONE and CON groups, GFR and Uflow did not change. Term CON, ONE and MULT responses to phenylephrine infusion were similar to the Preterm MULT increases. Conclusions: 1) Kidney immaturity in preterm newborns includes the absence of renal vascular responses to increases in MAP 2) Preterm newborns exposed to repetitive doses of BETA respond to increased MAP mimicing the term newborn response and 3) Renal maturation at term is not affected by early BETA exposure.

A Single Dose of Antenatal Betamethasone Enhances Isoprenaline and Prostaglandin E2-Induced Relaxation of Preterm Ovine Pulmonary Arteries

β-Adrenergic agonists and prostaglandin E₂ (PGE₂) play an important role in perinatal pulmonary circulation. We have determined the effect of antenatal glucocorticoid treatment on isoprenaline- and PGE₂-mediated relaxation of pulmonary arteries of newborn preterm lambs. Ovine fetuses (121 days of gestation; term = 150 days) received a single intramuscular dose of betamethasone (0.5 mg/kg) or saline. Fifteen hours after the injection, the lambs were delivered, ventilated for 3 h, and sacrificed. The fourth-generation pulmonary arteries were dissected and cut into rings for study. In endothelin-1-preconstricted vessels, isoprenaline, PGE₂, and forskolin (an activator of adenylyl cyclase) induced greater relaxations of pulmonary arteries of betamethasone-treated lambs than those of controls. 8-Bromo-cyclic adenosine monophosphate, a cell membrane permeable analogue of cyclic adenosine monophosphate, caused similar relaxation of all vessels. When stimulated with isoprenaline and PGE₂, the adenylyl cyclase activity of crude membrane preparations of pulmonary arteries treated with betamethasone was greater than that of controls. These results show that single-dose antenatal betamethasone treatment enhances relaxation of pulmonary arteries of preterm lambs induced by isoprenaline and PGE₂ and that an enhanced adenylyl cyclase activity contributes to the effect of betamethasone on pulmonary arteries of preterm lambs.

Effects of maternal dexamethasone therapy on fetal lung development in the rhesus monkey.

A large body of evidence demonstrates that antenatal glucocorticoids can accelerate fetal lung maturation. The purpose of this study was to delineate the optimal dose of dexamethasone and to determine whether a single- or multiple-injection regimen of the same total dexamethasone dosage was more effective in accelerating pulmonary development. Pregnant rhesus monkeys were injected with varying doses of dexamethasone or vehicle as either a single-bolus injection or as four separate injections, each spaced 12 hours apart. All maternal treatments were begun exactly 72 hours prior to delivery, and all fetuses were delivered by cesarean section at 135 +/- 1 days gestation. When a single injection of dexamethasone was used, fetal liver weight increased in a dose-related fashion. Fetal and maternal cortisol and fetal blood glucose concentrations were also influenced by increasing dexamethasone dosages. Fetal pulmonary phospholipids, however, were unchanged at all steroid doses examined. Multiple injections of dexamethasone generally produced more pronounced effects, even though the total dexamethasone dose remained the same. Thus, liver weight and fetal and maternal cortisol, glucose, and insulin levels were significantly influenced by the multiple administration of dexamethasone. In addition, total lung phosphatidylcholine, surfactant phosphatidylcholine, the surfactant-phosphatidylcholine-to-total-phosphatidylcholine ratio, and the surfactant-disaturated-phosphatidylcholine-to-total-lung-disaturated- phosphatidylcholine ratio were elevated after the multiple-injection regimen. A total dose of 0.5 mg dexamethasone/kg maternal body weight given in four separate injections appeared to produce the most beneficial results. These data suggest that low-dose, antenatal glucocorticoid treatment can effectively accelerate the biochemical maturation of the fetal lung.

Vitamin A deficiency and severe bronchopulmonary dysplasia in very low birthweight infants.

Preterm infants often have abnormally low serum vitamin A concentrations. Persistence of vitamin A deficiency for a prolonged postnatal period may contribute to the development of bronchopulmonary dysplasia. We retrospectively analyzed data from 22 infants with birthweight < or = 1250 g who had hyaline membrane disease requiring mechanical ventilation with oxygen and in whom serum vitamin A concentrations had been measured at the onset of enteral feeding and every 2 weeks thereafter. Thirteen infants (low serum vitamin A group) had one or more serum vitamin A concentrations < or = 11 mcg/dL at > 10 days of age. In 9 infants (higher serum vitamin A group) all serum vitamin A concentrations were > 11 mcg/dL at > 10 days of age. Mean birthweight, mean gestational age, sex, race, incidence of antenatal maternal glucocorticoid treatment and ventilatory support on the first day of life were similar for the two groups. Severe bronchopulmonary dysplasia was as defined as characteristic radiographic changes and either discharge from the hospital with supplemental oxygen or death from respiratory failure at > 28 days of age following mechanical ventilation with oxygen since birth. The incidence of severe bronchopulmonary dysplasia was significantly higher in the low serum vitamin A group (11/13, 3 deaths vs. 1/9, no deaths; p=0.001). The incidence of pulmonary air leak, the number of ventilator days, the number of days of postnatal glucocorticoid treatment for chronic lung disease, the number of episodes of suspected sepsis and the number of days of antibiotic treatment also were higher in the low serum vitamin A group. Low serum vitamin A group infants were older at the onset of enteral feeding (21 days vs. 8 days; p = 0.001) and during feeding their average daily enteral intake of vitamin A was lower (713 IU vs. 1255 IU; p = 0.001) when compared with infants in the higher serum vitamin A group. Our retrospective analysis of data from these infants confirms earlier reports from other workers that persistent marked vitamin A deficiency in very low birthweight infants is associated with a high incidence of severe bronchopulmonary dysplasia, delayed onset of enteral feeding and low enteral intake of vitamin A.

Antenatal Glucocorticoid Treatment Attenuates Immediate Postnatal Prostacyclin and Thromboxane Levels in Plasma of Very Preterm Lambs

The effect of antenatal glucocorticoid treatment on the production of cyclooxygenase metabolites was studied in very preterm lambs. Seven fetal lambs, 121 days of gestation, received a single dose of betamethasone, 0.5 mg/kg i.m., 48 h prior to delivery. Five age-matched controls received saline intramuscularly. Each fetus was delivered and ventilated for 3 h and sacrificed. Plasma was prepared from blood drawn from the umbilical cord of each fetus, and 60, 120 and 180 min after delivery. Mesenteric (MESA) and femoral (FEMA) arteries were isolated and incubated in Krebs' buffer for 10 min at 37 degrees C. Samples were extracted for prostacyclin (PGI2), and thromboxane (Tx)A2, purified by HPLC and measured by specific radioimmunoassay. Amounts of metabolites measured postnatally from betamethasone-treated preterm lambs were significantly lower (p < 0.05) than the amounts from saline lambs. Prostacyclin production by MESA and FEMA of betamethasone-treated lambs was lower than by vessels of saline-treated lambs. There was no difference in TxA2 production by vessels from the two groups of preterm lambs. Our data show that antenatal betamethasone treatment decreased systemic prostanoid production suggesting a decreased reactivity of the vascular membrane.

Australian collaborative trial of antenatal thyrotropin-releasing hormone (ACTOBAT) for prevention of neonatal respiratory disease

The addition of thyrotropin-releasing hormone (TRH) to antenatal glucocorticoid treatment of women at risk of preterm delivery has been reported to lower the risk of respiratory distress syndrome (RDS) in the infant. We have assessed the efficacy of 200 μg TRH in a multicentre randomised trial. 1234 women at 24 weeks to 31 weeks 6 days of gestation with a singleton or twin pregnancy and at risk of preterm delivery were randomly allocated to groups receiving 200 μg TRH or placebo intravenously every 12 h up to a maximum of four doses. Randomisation was stratified by duration of gestation and centre. All women received glucocorticoids. Clinical outcome is known for 1231 women and their 1397 infants. The frequencies of the main prespecified study outcomes RDS (relative risk 1·17 [95% Cl 1·00-1·36], p=0·05) and need for ventilation (1·15 [1·01-1·31], p=0·04) were higher in TRH-group infants than in control infants. The excess risk in the TRH group was greater in infants who were born more than 10 days after treatment. Multivariate analysis adjusting for duration of gestation at randomisation, time from randomisation to delivery, parity, history of perinatal death, and infant's sex did not affect the risk estimates. TRH administration was associated with increased risks of maternal nausea, vomiting, lightheadedness, and a rise in blood pressure to 140/90 mm Hg or higher. Antenatal TRH given with glucocorticoids to women at high risk of preterm delivery is associated with maternal and perinatal risks and cannot be recommended for widespread clinical use.

Preterm birth prevention: Where are we?

The purpose of this study was to review the current approaches to preventing preterm delivery. The problem of preterm birth was assessed by reviewing the different components that play a role in preterm birth prevention, excluding infection, antibiotic treatment, and tocolytic treatment. Prevention of preterm labor must initially discriminate those at risk. Positive predictive values of various approaches are currently not adequate enough to warrant intervention. Prevention modalities, in part because of poor prediction, are mostly unproved. Accurate diagnoses of preterm labor remains difficult and confuses analyses of tocolytic agents. Cervicovaginal fetal fibronectin, perhaps in combination with cervical evaluation, shows promise. Early detection programs remain controversial, but most reviews indicate that daily patient contact with high-risk patients gives cause for some optimism. Antenatal maternal glucocorticoid treatment at specific gestational ages improves neonatal outcome. The incidence of preterm birth is rising in the country. However, improved definition of the various components of the problem has provided an improved understanding of the problem. There is a new continuing effort and a search for new and innovative ways to address this vexing national problem.

Clinical aspects of antenatal glucocorticoid treatment for prevention of neonatal respiratory distress syndrome.

Main indications for antenatal administration glucocorticoid to pregnant women are premature contractions, hemorrhage during pregnancy, conditions of fetal distress and maternal diseases. There are some absolute or relative contraindications as well: severe forms of preeclampsia, diabetes mellitus, premature rupture of membranes, maternal and/intrauterine infections. In a retrospective evaluation of the data obtained at our institution of 637 nonrandomized cases from the years 1980-1985, we could demonstrate the dependence of the therapeutic results on the sex of the newborn. The RDS incidence is significantly different after betamethasone prophylaxis. It was 1/25 (4%) in girls compared to 13/31 (42%) in boys. A marked reduction of the RDS incidence is only detectable after betamethasone therapy from the 32nd to the 34th week of gestation. Thus we recommend RDS prophylaxis for all patients with premature contraction, mainly between the 32nd and 34th week of pregnancy. In addition, it should be given in cases of confirmed lung immaturity. Special restrictions are necessary in cases of preeclampsia, eclampsia, diabetes and confirmed maternal infections. In the group of diabetes or preeclampsia patients an RDS prophylaxis should only be given, if at all, when it can be performed under intensive care conditions.

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.

Alternatives to the antenatal glucocorticoid treatment for the prevention of respiratory distress syndrome.

Various substances and methods are used as alternatives to corticoids for stimulating antenatal pulmonary maturation. This study discusses thyroid hormones, intralipid, ambroxol, carnitine, theophylline (aminophylline) and betasympathomimetic agents.

The Prevention of Hyaline Membrane Disease: New Concepts and Approaches to Therapy

New approaches to hyaline membrane disease have emerged in recent years. These developments are principally attributable to advances in our understanding of the following: (1) the pathophysiology and pathogenesis of HMD in relationship to pulmonary surfactant, (2) fundamental aspects of fetal lung development, including the movement of surfactant phospholipids from fetal pulmonary fluid to the amniotic space, (3) mechanisms for accelerating lung maturation, particularly with maternally administered prenatal glucocorticoids, and (4) ventilatory techniques effective in protecting and conserving alveolar surfactant by the continuous application of end expiratory pressure. Prenatal assessment of the risk for developing hyaline membrane disease is now routinely possible by amniocentesis and analysis of the ratio of lecithin to sphingomyelin in amniotic fluid. Such predictability, coupled with the ability to postpone delviery, allows the perinatologist in some instances to provide the fetus with ample opportunity for lung development in utero. Recent clinical trials around the world with pregnant women in premature labor document a significantly lower incidence of hyaline membrane disease after antenatal glucocorticoid treatment. In neonates with the disease weighing more than 1500 gm, it is now established that reduced mortality rates accrue from the use of end expiratory positive pressure. These clinical advances offer great promise in changing the nature of HMD management from procedures that are largely supportive to approaches that are truly preventative.