Use Of Antenatal Glucocorticoids Research Articles

Analysis of risk factors of early intraventricular hemorrhage in very-low-birth-weight premature infants: a single center retrospective study

BackgroundThis study aimed to determine the risk factors of early intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) premature infants in China to guide early interventions and improve the survival and quality of life of these infants.MethodsData on 421 VLBW premature infants admitted to the neonatal intensive care unit of Tianjin Central Hospital of Gynecology Obstetrics between July 2017 and July 2019 were retrospectively evaluated. Data on head ultrasound results, maternal pregnancy complications, and perinatal conditions were reviewed to evaluate the association between maternal and neonatal factors and the development and severity of IVH.ResultsUnivariate analysis showed that the incidence of early IVH was significantly higher in neonates with early gestational age, delivered after spontaneous labor, low birth weight, 5-minute Apgar score ≤ 7, invasive mechanical ventilation, and early onset sepsis (χ2 = 11.087, 16.868, 4.779, 11.170, 6.655, and 6.260, respectively; P < 0.05), but it was significantly lower in the presence of gestational hypertension (χ2 = 4.373, P = 0.037). In addition, severe IVH was significantly associated with early gestational age, low birth weight, 5-minute Apgar score ≤ 7, and neonatal sepsis (χ2 = 11.599, 8.263, 11.172, and 7.749, respectively; P < 0.05). Logistic regression analysis showed that antenatal glucocorticoid use was associated with significantly reduced incidence of severe IVH (OR = 0.095, 95% CI = 0.012–0.739, P = 0.024).ConclusionAppropriate mode of delivery may effectively reduce the incidence of IVH in VLBW premature infants. The antenatal glucocorticoid use may also protect against severe IVH. The focus on steroid prophylaxis, mode of delivery and prevention of perinatal asphyxia should be stressed in China.

Antenatal Glucocorticoids in Low-Resource Settings—Who, When, and Where?

(N Engl J Med. 2020;383:2584–2585) Glucocorticoid therapy has been long known to improve neonatal outcomes in preterm birth. The data supporting the use of antenatal glucocorticoids largely comes from high-resource countries. The Antenatal Corticosteroids Trial (ACT) published in 2015 investigated the use of antenatal dexamethasone in settings with limited access to obstetricians and neonatal intensive care. ACT found antenatal dexamethasone did not lower mortality among neonates with a birth weight below the fifth percentile (a proxy for preterm birth), but instead increased overall neonatal mortality compared with placebo (27.4 vs. 23.9 deaths/1000 live births) and increased the incidence of suspected maternal infection (3% to 2%).

Antenatal Dexamethasone for Early Preterm Birth in Low-resource Countries

(N Engl J Med. 2020;383:2514–2525) Antenatal glucocorticoids are a common intervention in preventing adverse outcomes associated with preterm birth. The evidence supporting this intervention is based on trials in high-resource settings, however, and a 2015 trial in low-resource countries found scaling up this intervention caused an increase in neonatal death, stillbirth and suspected maternal infection. The World Health Organization (WHO) has issued guidelines restricting the use of antenatal glucocorticoids to certain situations. This study, the WHO ACTION-1 (Antenatal Corticosteroids for Improving Outcomes in Preterm Newborns) trial, aimed to determine the levels of safety and efficacy of dexamethasone in women at risk for early preterm birth in low-resource countries compared with placebo.

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries

(Abstracted from N Engl J Med 2020;383:2514–2525) The use of antenatal glucocorticoids to reduce infant morbidity and mortality associated with preterm birth has been supported by a number of studies conducted in high-resource countries. However, a 2015 population-based trial conducted in low-resource countries called their use into question.

Risk factors for endotracheal intubation during resuscitation in the delivery room among very preterm infants

Objective To explore the risk factors for endotracheal intubation during resuscitation in the delivery room among very preterm infants. Methods A retrospective analysis was performed for 455 very preterm infants who were admitted to the neonatal intensive care unit from January 2017 to December 2019. They were divided into an intubation group (n=79) and a non-intubation group (n=376) according to whether endotracheal intubation was performed during resuscitation. The risk factors for endotracheal intubation during resuscitation were evaluated by multivariate logistic regression analysis. Results The intubation rate was 17.4% (79/455). Compared with the intubation group, the non-intubation group had significantly higher gestational age, birth weight, and rates of caesarean birth, delayed cord clamping (DCC), resuscitation quality improvement, regular use of antenatal glucocorticoids in mothers and premature rupture of membranes > 18 hours (P Conclusions Very preterm infants with younger gestational age, birth weight

A multicenter study of the birth condition of preterm infants and the causes of preterm birth in Henan Province, China

OBJECTIVE To investigate the birth condition of preterm infants and the causes of preterm birth in Henan Province, China, and to provide a basis for the prevention and treatment of preterm birth. METHODS An epidemiological investigation was conducted for live-birth preterm infants who were born in 53 hospitals in 17 cities of Henan Province from January 1, 2019 to December 31, 2019 to investigate the incidence rate of preterm birth, the distribution of gestational age and birth weight, the use of antenatal glucocorticoids, and the causes of preterm birth. RESULTS The incidence rate of preterm birth was 5.84% (12 406/212 438) in the 53 hospitals. The proportions of preterm infants with gestational ages of < 28 weeks, 28 - < 32 weeks, 32 - < 34 weeks, and 34 - < 37 weeks were 1.58% (196/12 406), 11.46% (1 422/12 406), 15.18% (1 883/12 406), and 71.78% (8 905/12 406) respectively. The proportions of preterm infants with birth weights of < 1 000 g, 1 000- < 1 500 g, 1 500- < 2 500 g, 2 500- < 4 000 g, and ≥ 4 000 g were 1.95% (240/12 313), 8.54% (1 051/12 313), 49.53% (6 099/12 313), 39.59% (4 875/12 313), and 0.39% (48/12 313) respectively. The infants born by natural labor accounted for 28.76% (3 568/12 406), and those born by cesarean section accounted for 70.38% (8 731/12 406). The rate of use of antenatal glucocorticoids was 52.52% (6 293/11 983) for preterm infants and 68.69% (2 319/3 376) for the preterm infants with a gestational age of < 34 weeks. Iatrogenic preterm labor was the leading cause of preterm birth[40.06% (4 915/12 270)], followed by spontaneous preterm birth[30.16% (3 701/12 270)] and preterm birth due to premature rupture of membranes[29.78% (3 654/12 270)]. The top three causes of iatrogenic preterm birth were hypertensive disorders of pregnancy[47.12% (2 316/4 915)], fetal intrauterine distress[22.85% (1 123/4 915)], and placenta previa/placental abruption[18.07% (888/4 915)]. CONCLUSIONS There is a relatively low incidence rate of preterm birth in Henan Province, and late preterm infants account for a relatively high proportion. Iatrogenic preterm birth is the main cause of preterm birth in Henan Province, and hypertensive disorders of pregnancy and fetal intrauterine distress are the main causes of iatrogenic preterm birth.

Present and Future of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disorder among infants born extremely preterm. The pathogenesis of BPD involves multiple prenatal and postnatal mechanisms affecting the development of a very immature lung. Their combined effects alter the lung’s morphogenesis, disrupt capillary gas exchange in the alveoli, and lead to the pathological and clinical features of BPD. The disorder is ultimately the result of an aberrant repair response to antenatal and postnatal injuries to the developing lungs. Neonatology has made huge advances in dealing with conditions related to prematurity, but efforts to prevent and treat BPD have so far been only partially effective. Seeing that BPD appears to have a role in the early origin of chronic obstructive pulmonary disease, its prevention is pivotal also in long-term respiratory outcome of these patients. There is currently some evidence to support the use of antenatal glucocorticoids, surfactant therapy, protective noninvasive ventilation, targeted saturations, early caffeine treatment, vitamin A, and fluid restriction, but none of the existing strategies have had any significant impact in reducing the burden of BPD. New areas of research are raising novel therapeutic prospects, however. For instance, early topical (intratracheal or nebulized) steroids seem promising: they might help to limit BPD development without the side effects of systemic steroids. Evidence in favor of stem cell therapy has emerged from several preclinical trials, and from a couple of studies in humans. Mesenchymal stromal/stem cells (MSCs) have revealed a reparatory capability, preventing the progression of BPD in animal models. Administering MSC-conditioned media containing extracellular vesicles (EVs) have also demonstrated a preventive action, without the potential risks associated with unwanted engraftment or the adverse effects of administering cells. In this paper, we explore these emerging treatments and take a look at the revolutionary changes in BPD and neonatology on the horizon.

Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells.

Preterm infants frequently suffer from respiratory distress syndrome (RDS), possibly due to lower expression of epithelial Na+ channels (ENaC). RDS incidence is sex-specific, affecting males almost twice as often. Despite the use of antenatal glucocorticoids (GCs), the sex difference persists. It is still controversial whether both sexes benefit equally from GCs. We previously showed that Na+ transport is higher in female compared with male fetal distal lung epithelial (FDLE) cells. Since GCs increase Na+ transport, we hypothesized that their stimulating effect might be sex-specific. We analyzed FDLE cells with Ussing chambers and RT-qPCR in the presence or absence of fetal serum. In serum-free medium, GCs increased the ENaC activity and mRNA expression, independent of sex. In contrast, GCs did not increase the Na+ transport in serum-supplemented media and abolished the otherwise observed sex difference. Inhibition of the GC receptor in the presence of serum did not equalize Na+ transport between male and female cells. The GC-induced surfactant protein mRNA expression was concentration and sex-specific. In conclusion, female and male FDLE cells exhibit no sex difference in response to GCs with regard to Na+ transport, and GR activity does not contribute to the higher Na+ transport in females.

The effects of antenatal glucocorticoid exposure on fetal and neonatal skin maturation.

The use of antenatal glucocorticoids in women with preterm labor has dramatically improved outcomes for premature infants. The most commonly used antenatal glucocorticoids are betamethasone and dexamethasone. Glucocorticoids accelerate fetal lung growth by several mechanisms, including the maturation of type II pneumocytes enabling surfactant production. Furthermore, the lipids in the lung share similarity with those in the skin. Therefore, antenatal administration of glucocorticoids may have effects on the structure and function of the developing epidermal barrier in fetuses and neonates. We performed a systematic review to characterize these effects, identifying 11 studies (six animal and five human studies). Five out of the six animal studies used a rodent model for investigating the effects of antenatally administered glucocorticoids, while the other used an ovine model. Antenatally administered glucocorticoids accelerated skin maturation in animal studies, but studies of human fetuses found conflicting results. None of the reviewed studies compared the effects of different types of glucocorticoids. More human studies are needed to fully understand the effects of antenatal steroids. However, as the antenatal use of glucocorticoids in preterm pregnancies has become part of standard clinical practice, it would be unethical to carry out a large randomized controlled trial. We may have to rely on animal models to improve our understanding of the effects of antenatal glucocorticoid exposure on the fetal and neonatal skin maturation.

Prenatal betamethasone exposure and psychopathology risk in extremely low birth weight survivors in the third and fourth decades of life

BackgroundMortality rates among extremely low birthweight (ELBW) infants have declined since the advent of antenatal glucocorticoid use. However, the long term neuropsychiatric effects of exposure are not well understood. We utilized the world's oldest longitudinally followed cohort of ELBW survivors to compare psychopathology over two decades in adulthood in those exposed to prenatal betamethasone and those who were not. MethodsELBW survivors (n=179) and matched normal birth weight (NBW) controls (n=145) completed the Young Adult Self-Report questionnaire at 22–26 and 29–36 years, and the Beck Depression and Anxiety Inventories at 29–36 years. Symptom levels and rates of clinically significant psychiatric problems were compared in ELBW survivors whose mothers were administered steroids during pregnancy (ELBW-S n=63), ELBW participants who were not (ELBW-NS, n=79), and NBW controls. ResultsAt 22–26, ELBW-S had higher levels of anxiety, depressive, and avoidant personality symptoms, and a 3 to 5-fold increase in the odds of clinically significant levels of these problems compared to NBW controls, whereas ELBW-NS did not. These associations were maintained at 29–36, when ELBW-S participants exhibited a 3 to 10-fold increase in the odds of clinically significant anxiety and avoidant personality problems compared to NBW controls. At both time points, the odds of clinically significant anxiety problems were more than 3 times higher among ELBW-S than in ELBW-NS. ConclusionELBW adults exposed to prenatal betamethasone manifest higher levels of anxiety and depression than those who were not, and may represent a group of preterm survivors at particularly high psychiatric risk.

Programming effects of glucocorticoids.

Fetal glucocorticoid overexposure is a key potential mechanism underlying the link between low birthweight and later life diseases. The fetus is protected from high maternal glucocorticoid levels by the placental enzyme 11β-hydroxysteroid dehydrogenase type 2. Antenatal glucocorticoid administration to women at threat of preterm labor, and high endogenous maternal glucocorticoid levels during pregnancy associate with lower birthweight. Long-term consequences for offspring include hypothalamic-pituitary-adrenal axis activation, increased metabolic and cardiovascular disorders, and neurodevelopmental sequelae. Strategies are needed to limit antenatal glucocorticoid use to those most at risk of preterm labor and to identify those most at risk of future disease.

Neonatology Specialty Grand Challenge

Neonatology Specialty Grand Challenge

Antenatal corticosteroids for fetal lung maturation in threatened preterm delivery: indications and administration

Antenatal maternal administration of corticosteroids has been shown to reduce morbidity and mortality rates in preterm delivery. Threatened spontaneous or medically indicated preterm delivery for maternal or fetal indications between 24 and 34 weeks of gestation with unknown fetal lung maturity status are indications for antenatal corticosteroid administration. Recent studies have challenged current practice of antenatal glucocorticoid use. The goal of this expert letter is to provide recommendations based for the clinical use of antenatal glucocorticoids based on the current evidence from published studies. The published literature (PubMed search), as well as the recommendations of other national societies, has been searched and taken into consideration for these recommendations. The standard regimen of antenatal corticosteroids involves a single course of 2 × 12 mg betamethasone administered intramuscularly within 24 h. The administration of corticosteroids usually is performed between 24 and 34 weeks gestation. However, under particular circumstances it may be beneficial even at 23 weeks and at 35-36 weeks of gestation. The evidence to date is clearly against the routine administration of multiple antenatal steroid courses. In special clinical situations, a second course of betamethasone ("rescue course") may be justifiable. Tocolysis during administration of steroids is not routinely indicated in the absence of contractions, cervical shortening or rupture of membranes.

Antenatal betamethasone alters vascular reactivity in adult female ovine cerebral arteries.

Although the use of antenatal glucocorticoids has resulted in decreased neonatal morbidity/mortality, recent animal studies have raised concerns regarding adverse effects of these medications on postnatal cardiovascular function. We hypothesized that antenatal betamethasone (Beta) exposure alters cerebral vascular reactivity in adult female sheep. We observed that K-induced constriction was comparable in middle cerebral artery (MCA) from Beta-exposed animals and age-matched controls. Pressure-induced constriction was significantly attenuated in MCA from Beta-exposed compared with control sheep. Inhibition of NOS significantly augmented pressure-induced constriction in MCA from both Beta-exposed and control sheep, whereas cyclooxygenase (COX) inhibition augmented pressure-induced constriction only in MCA from Beta-exposed sheep. Furthermore, NOS and COX inhibition significantly attenuated bradykinin (BK)-induced dilation in MCA from both Beta-exposed and control sheep. However, there seemed to be a greater contribution of both NOS and COX to BK-induced dilation in Beta-exposed compared with control MCA. Our findings demonstrate that fetal exposure to a clinically relevant course of Beta alters cerebral vascular tone and reactivity in adult female sheep.

Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies

Recent reports suggest that specific care strategies improve survival of infants with congenital diaphragmatic hernia (CDH). This review presents details of care from centers reporting high rates of survival among CDH infants. We conducted a MEDLINE search (1995 to 2006) and searched all citations in the Cochrane Central Register of Controlled Trials. Studies were included if they contained reports of >20 infants with symptomatic CDH, and >75% survival of isolated CDH. Thirteen reports from 11 centers met inclusion criteria. Overall survival, including infants with multiple anomalies, was 603/763 (79%; range: 69 to 93%). Survival for isolated CDH was 560/661 (85%; range: 78 to 96%). The frequency of extracorporeal membrane oxygenation (ECMO) use for isolated CDH varied widely among reporting centers 251/622 (40%; range: 11 to 61%), as did survival for infants with isolated CDH placed on ECMO: 149/206 (73%; range: 33 to 86%). There was no suggestion of benefit from use of antenatal glucocorticoids given after 34 weeks gestation or use of postnatal surfactant. Low mortality was frequently attributed to minimizing lung injury and adhering to center-specific criteria for ECMO. Use of strategies aimed at minimizing lung injury, tolerance of postductal acidosis and hypoxemia, and adhering to center-specific criteria for ECMO were strategies most consistently reported by successful centers. The literature lacks randomized clinical trials of these or other care strategies in this complex patient population; prospective studies of safety and long-term outcome are needed.

Scientific rationale for the use of antenatal glucocorticoids to promote fetal development.

After completing this article, readers should be able to: 1. Describe the scope of physiologic effects of antenatal corticosteroids on the developing fetus. 2. Describe the role for endogenous corticosteroids in fetal maturation. 3. Delineate the components of surfactant that are induced with corticosteroid treatment. 4. Describe the time course of pulmonary effects following administration of corticosteroids in the fetal lamb. 5. Delineate recommended treatment regimens and levels of plasma glucocorticoid activity in human infants. Following publication of the report of the National Institutes of Health Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation in 1994, antenatal corticosteroid therapy has become routine practice in the United States and most other countries. This therapy had its origins in the pioneering observations of Liggins in 1969, who reported the unexpected viability of prematurely delivered lambs after treatment with corticosteroid in utero. Since then, much has been learned about the biochemical and physiologic effects as well as the mechanisms of corticosteroid action in the developing lung and other tissues. This review summarizes the evidence that constitutes the scientific rationale for clinical use of antenatal treatment and discusses pharmacokinetic issues related to the recommended doses of corticosteroid. ### PHYSIOLOGIC EFFECTS IN THE LUNG The physiologic effects of glucocorticoids in the developing lung have been investigated extensively in various animal models (Table 1⇓ ). In initial studies with rabbits and lambs, corticosteroid therapy was found to stimulate structural development of lung parenchyma involving both airspace lining cells (differentiation into surfactant-producing type II cells) and the mesenchyme (condensation with narrowing of saccular septae). When viewed by electron microscopy, the ultrastructure of airspace epithelial cells in glucocorticoid-treated cultured fetal lung resembles that of mature type II cells of adult lung, containing well-developed lamellar bodies and microvillae. Glucocorticoids also increase lung compliance and maximal volume independent of the effects of increased surface-active material, presumably reflecting …

Clinical use of antenatal corticosteroids: benefits and risks.

After completing this article, readers should be able to: 1. Describe the rationale for the use of antenatal corticosteroids for human fetal maturation. 2. Delineate recommendations of the 1994 National Institutes of Health Consensus Conference on Antenatal Corticosteroids. 3. Review areas of controversy in the clinical use of antenatal corticosteroids. 4. Describe the potential risks of multiple courses of antenatal corticosteroids. 5. Delineate current recommendations for clinical use of antenatal corticosteroids to promote fetal maturation. Glucocorticoid administration initially was appreciated as a method for accelerating development of the intestine more than 40 years ago. Since that time, developmental effects of these agents have been defined in at least 16 tissues of mammals. More than 30 years ago, while studying the mechanism of initiation of labor in sheep, Liggins made the observation that infusion of corticosteroids into fetal lambs was associated with improved survival and decreased lung disease in animals delivered preterm. Subsequently, numerous studies in cell culture, animal models, and human fetal tissue have delineated the multiple effects of glucocorticoids on the developing lung. These include increases in both the total tissue and alveolar surfactant pools; a decrease in vascular permeability, with less protein leak into the alveolar spaces; enhanced clearance of lung water; maturation of parenchymal structure; increase in lung compliance and maximal lung volume; enhanced response to surfactant treatment; and improvement in respiratory function, outcome, and survival. (See accompanying article on scientific rationale for use of antenatal glucocorticoids.) In 1972, the first randomized clinical trial of administration of antenatal corticosteroids (ANCS) in humans demonstrated decreased mortality and a decreased incidence of respiratory distress syndrome (RDS) in preterm infants born at less than 34 weeks’ gestation, who were treated with betamethasone for at least 24 hours before delivery. Over the ensuing 20 years, multiple clinical investigations continued to document the effectiveness of ANCS on …

Increased antenatal glucocorticoid use decreases mortality and morbidity in the NICHD Neonatal Research Network's very low birth weight (VLBW) infants.• 1269

Increased antenatal glucocorticoid use decreases mortality and morbidity in the NICHD Neonatal Research Network's very low birth weight (VLBW) infants.• 1269

Glucocorticoid use in patients with preterm premature rupture of the fetal membranes

Antenatal glucocorticoid use in patients with preterm premature rupture of membranes (PPROM) is controversial. The majority of prospective, randomized studies on antenatal glucocorticoid use evaluate the effect of this intervention on preterm infants delivered due to multiple, diverse etiologies, only one of which is PPROM [corrected]. These studies present a variety of conflicting conclusions; meta-analysis indicates a potential benefit of steroids in the reduction of RDS, intraventricular hemorrhage, and mortality. Meta-analysis of studies specifically evaluating pregnancies complicated by PPROM demonstrates a significant reduction in RDS; however, this effect is primarily due to the work of a single author with a potentially atypical study population [corrected]. The remaining studies fail to show a benefit of steroids. The strongest argument for steroid use in patients with PPROM is extrapolation of data from studies of patients delivered preterm due to a variety of etiologies, not just PPROM. While such an extrapolation is currently recommended by the NIH Consensus Development Panel, it may be premature to assume that the same pathophysiological mechanisms and the same propensity for benefit from steroids occur in these different populations. Further studies are necessary before glucocorticoids can be confidently recommended in pPROM.

Scientific basis and therapeutic regimens for use of antenatal glucocorticoids: Ballard P.L.; Ballard R.A. Am J Obstet Gynecol 1995 173/1 (254–262)

Scientific basis and therapeutic regimens for use of antenatal glucocorticoids: Ballard P.L.; Ballard R.A. Am J Obstet Gynecol 1995 173/1 (254–262)