Antenatal glucocorticoids and the developing brain: mechanisms of action

Glucocorticoids are critical for normal brain development. There is no doubt that prenatal treatment with synthetic glucocorticoid affords great benefit to the preterm infant. However, animal studies, now carried out in many species, indicate that there may be some long-term physiological costs of early exposure to excess glucocorticoid, and that these appear sex-dependant. Further, the effects may not become apparent until later life. Given the dynamics of corticosteroid receptor systems in late gestation, it is likely that there are critical windows of development when specific regions of the brain are more sensitive to the influence of synthetic glucocorticoid. Once such windows have been identified it will be possible to target prenatal treatments, so as to maximize benefit and reduce risk of long-term effects. Notwithstanding, the data reviewed below indicate that caution should be exercised in the use of multiple course glucocorticoid therapy during pregnancy.     

Antenatal glucocorticoids and renal function after birth

Antenatal glucocorticoid treatment is widely used in cases of threatening preterm delivery. Both human and animal studies have confirmed that glucocorticoids promote pulmonary maturation in fetuses. Several studies indicate that prenatal glucocorticoids also stimulate renal maturation. Although the current knowledge about the effects of glucocorticoids on kidney function is mainly concentrated on short-term effects, there are animal studies suggesting that antenatal glucocorticoid treatment may also cause permanent changes in kidney morphology and renal function. It still remains to be investigated if antenatal glucocorticoid treatment induces long-term effects in humans.     

Antenatal therapies and the developing brain

This chapter presents a review of basic science and human studies of two commonly used pharmacologic agents (antenatal steroids and magnesium sulfate), in pregnancies at risk of preterm delivery, and examines the effects of these therapies on the developing brain. Very low birthweight (VLBW) infants are known to be at risk of both short-term and long-term neurodevelopmental sequelae; therefore, an understanding of the mechanisms contributing to both neuroprotective and neurotoxic effects of antenatal therapies on the immature brain and potential effects on long-term outcome are critical. Although the short-term beneficial effects of a single course of antenatal steroids are well documented, the experimental animal literature suggests detrimental effects on neurodevelopment of multiple doses. In addition, clinical studies of repeat doses suggest a negative impact on head and brain growth. The animal and human data on the effects of MgSO₄are also mixed with both beneficial effects or no effects on neurodevelopment. This review will discuss the potential impact of single versus multiple doses and timing of doses on the brain.     

Antenatal steroids and the developing brain

Randomised clinical trials show that two injections of corticosteroid into the mother before preterm delivery reduce respiratory distress syndrome, neonatal mortality, and intraventricular haemorrhage. However, repeated courses of antenatal steroid are not backed by such evidence of safety and efficacy. Animal studies have shown that maternal corticosteroid delays myelination and reduces the growth of all fetal brain areas particularly the hippocampus. Corticosteroids may reduce or enhance hypoxic-ischaemic injury to the developing brain depending on timing and dosage. Clinical trials of maternally administered corticosteroid show no evidence of increased disability on follow up but numbers are small. Postnatal trials of dexamethasone when brain maturity is still preterm show a significant increase in later disability in the dexamethasone treated groups. There is evidence from randomised trials, retrospective data, experiments on pregnant mice, and the chemical make up of the preparations that betamethasone may be safer and more protective of the immature brain than dexamethasone. Single course corticosteroid treatment before preterm delivery must still be recommended as a life saving and cost effective intervention, but clinicians may wish to change from using dexamethasone to betamethasone. In view of the animal and postnatal data, clinicians should be cautious with repeated courses of antenatal corticosteroids and repetition may be unnecessary for lung maturity.     

Antenatal glucocorticoids attenuate activation of the inflammatory reaction and clotting in preterm lambs

Recently we have shown that activation of inflammatory reaction and clotting can be found immediately after delivery in preterm lambs ventilated for respiratory distress syndrome (RDS). To investigate whether antenatal glucocorticoids would attenuate postnatal activation of the inflammatory reaction and clotting, we studied ventilated preterm lambs delivered by cesarean section, 24 h after antenatal administration of betamethasone or placebo. Blood was sampled before clamping the cord, 5, 10, and 15 min after delivery, and 2-hourly afterwards. Blood was used to determine oxygenation index, alveolar - arterial partial O(2) difference (AaDO(2)), AP50 titer (see text), polymorphonuclear leukocytes (PMNs), beta-glucuronidase, thrombin inhibition, activated partial thromboplastin time, and clot lysis time. Bronchoalveolar lavage fluid was sampled before clamping the cord and 30 min and 1, 2, 4, 6 and 8 h after delivery and was analyzed for elastase, thrombin, and protein. After removal of the lungs, static compliance and water content of the lungs were determined. We found that betamethasone-treated lambs had lower oxygenation index and AaDO(2) than controls. At birth, PMN levels were higher, and the beta-glucuronidase level was lower after betamethasone treatment. PMNs and beta-glucuronidase did not change in betamethasone-treated lambs, in contrast to controls. Thrombin inhibition, activated partial thromboplastin time, and clot lysis time did not change in betamethasone-treated lambs, in contrast to controls. In both groups, elastase and protein levels in bronchoalveolar lavage fluid increased; the thrombin level increased in controls. The static compliance was better, and the water content of the lung was lower in the betamethasone-treated lambs. We conclude that early systemic activation of inflammatory reaction and clotting in preterm lambs with RDS are attenuated by antenatal betamethasone administration. Whether this is a direct effect of betamethasone on the inflammatory reaction or a result of a reduced ventilatory support because of less severe RDS after antenatal betamethasone treatment remains to be elucidated.     

Antenatal glucocorticoids increase early total thyroxine levels in premature infants

BACKGROUND: Hypothyroxinemia is associated with adverse neonatal outcomes including white matter damage, cerebral palsy, poor neurodevelopment and death. It has become increasingly important to understand the natural history and modifiers of thyroid function in the premature infant. It is standard obstetrical practice to offer antenatal glucocorticoids to pregnant women with threatened preterm delivery. Few studies have investigated the effect of antenatal glucocorticoids on neonatal thyroid function. OBJECTIVE: To examine the association between antenatal exposure to glucocorticoids and early total thyroxine (T4) levels among extremely premature infants. METHODS: We studied 521 infants born at 4 medical centers. Entry criteria included a gestational age of 23-28 weeks and a serum thyroxine level obtained in the first postnatal week. Receipt of antenatal glucocorticoids was recorded as none, partial, or complete. A complete course consisted of two doses of betamethasone or four doses of dexamethasone within a 48-hour period between 2 and 7 days of delivery. Early total T4 levels were obtained from state-mandated newborn screening programs. RESULTS: Controlling for potential maternal, perinatal and neonatal confounding variables, infants exposed to a complete course of antenatal glucocorticoids had total T4 levels 0.8 microg/dl higher than their peers who were not exposed to a complete course of antenatal glucocorticoids (p = 0.03). CONCLUSIONS: Extremely premature infants who received a complete course of antenatal glucocorticoids had significantly higher total thyroxine levels in the first postnatal week. Maternal, perinatal, and early neonatal variables did not completely explain this association. We speculate that antenatal glucocorticoids influence early neonatal thyroid function.     

Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies

In recent years, many clinicians have prescribed repeated courses of glucocorticoids to pregnant women at risk of early preterm birth. The published literature has provided reassurance from randomized controlled trials that single-course treatment improves postnatal lung function without deleterious consequences, but we do not yet have data from randomized trials designed specifically to investigate the effects of repeated courses. Data from animal studies have, for many years, provided evidence that prenatal exposure to glucocorticoids restricts fetal growth and, more recently, has suggested a role in programming the individual to adult disease. Multivariate analyses from non-randomized cohorts have also suggested associations between repeated treatments and reduced birth weight, but we await results from randomized controlled trials currently in progress to provide more definitive answers. Regardless of any effect on growth, the possibility that adult health and disease may be programmed by fetal exposure to glucocorticoids will ensure our need to balance the ability of these agents to improve newborn survival with the potential consequences in later life.     

Antenatal glucocorticoids alter postnatal preterm lamb renal and cardiovascular responses to intravascular volume expansion

We assessed renal and cardiovascular function in preterm newborn lambs after antenatal glucocorticoid exposure. Pregnant ewes were randomly assigned to receive betamethasone or saline via either direct fetal or maternal injection at 122 d gestation. Lambs were delivered 15 h later, and cardiovascular and renal function was assessed. Two hours after delivery, baseline urine flow, urinary sodium excretion, and urinary osmolar clearance were similar in all groups. Volume expansion (saline, 2.5% of body weight, for 10 min) increased values for urine flow (0.23 +/- 0.04 to 0.58 +/- 0.09 mL x min(-1) x kg(-1)), urinary sodium excretion (29.7 +/- 5.8 to 76.2 +/- 12.3 microEq x min(-1) x kg(-1)), and osmolar clearance (12.2 +/- 1.2 to 24.3 +/- 1.6 mL/100 mL GFR) in the fetal group. Increases in urine values were also observed in the maternal group, but control values did not change significantly. Mean arterial pressure was increased in both betamethasone-treated groups relative to controls. Short-term antenatal betamethasone exposure 1) augments preterm newborn kidney adaptive responses to acute volume expansion, and 2) increases postnatal blood pressure in preterm newborn lambs.     

Antenatal care in developing countries: the need for a tailored model

In developed countries, 98% of all women receive prenatal care and 94% give birth under the supervision of skilled healthcare practitioners with timely access to appropriate emergency treatment if complications arise. In contrast, large numbers of pregnant women in Africa and Asia do not receive adequate prenatal care and lack skilled attendance at birth. In developing countries quality of prenatal care is often scarce: models of care adopted in the western world and exported to the developing world have not been monitored early enough to discover their weak points promptly. This blind attitude has transformed antenatal care into an empty and useless ritual, and explains why antenatal care programmes continue to be unsuccessful, being inappropriate to the specific situation. A mix of educational and cultural factors together with persistent lack of resources in a global critical situation all contribute to the poor results of antenatal care programmes. Antenatal care services should be free of charge, planned and implemented within the community, cost-effective, and should yield evidence-based quality care. They should also include information for the patient and family members, provide affordable treatment of existing conditions, and warrant referral for complications.     

产前应用糖皮质激素预防足月择期剖宫产儿呼吸窘迫综合征系统评价和Meta分析

目的：系统评价产前应用糖皮质激素（GC）预防足月择期剖宫产新生儿呼吸窘迫综合征（RDS）的有效性和安全性。 方法：计算机检索PubMed、Embase、Cochrane图书馆、ClinicalTrials.gov、中国生物医学文献服务系统（CBM）、万方数据库、中国知网（CNKI）和维普期刊数据库（VIP）,纳入足月妊娠择期剖宫产的孕妇产前给予GC预防新生儿RDS的RCT,试验组产前给予GC治疗（药物种类、剂量、给药途径、疗程不作限制）,对照组给予安慰剂或为空白对照。采用主题词与自由词相结合的方式进行检索,检索时间均为建库至2018年4月19日。主要结局指标为新生儿RDS发生率和新生儿病死率,次要指标为新生儿暂时性呼吸增快（TTN）发生率、新生儿呼吸困难发生率、因呼吸困难入住NICU率、新生儿败血症发生率、产妇感染率及不良反应发生率。按照Cochrane手册推荐的RCT的偏倚风险评估工具评价纳入文献的偏倚风险。采用RevMan5.3软件进行Meta分析。 结果：共纳入4篇RCT文献3 893例单胎新生儿。4篇文献质量中等。Meta分析显示,试验组和对照组新生儿RDS发生率差异有统计学意义（OR=0.45,95%CI：0.24～0.83）,新生儿病死率差异无统计学意义;试验组和对照组TTN发生率（OR=0.41,95%CI：0.29～0.59）、新生儿因呼吸困难入住NICU率（OR=0.42,95%CI：0.29～0.63）和新生儿呼吸困难发生率（OR=0.34,95%CI：0.22～0.53）差异均有统计学意义。1篇文献报告了新生儿败血症发生率和产妇感染率,两组差异均无统计学意义。产前应用GC,并未引起母亲严重的不良反应率。 结论：基于现有临床证据,产前使用1疗程的GC可以降低足月单胎择期剖宫产儿RDS风险。     

Antenatal treatment with corticosteroids affects mRNA expression of dopamine D1 and D2 receptors in the striatum of developing rabbit

The expression levels of dopamine D1 and D2 receptor mRNA have been investigated using Northern blot analysis in developing rabbit striatum after antenatal exposure to betamethasone. Pregnant rabbits were given either 0.1 mg/kg betamethasone or 0.1 mg/kg saline doses twice within 24 h. Dopamine D1 receptor mRNA levels were found significantly higher in the fetuses exposed to antenatal betamethasone than in the saline-treated controls. After birth, dopamine D1 and D2 receptor mRNA levels were both significantly lower in 1- and 25-day-old treated pups but recovered to normal levels in adulthood. These data suggest that antenatal exposure to betamethasone can lead to lasting abnormalities.     

Antenatal care and perinatal mortality

There were 1092 deliveries in 1982 at CRHS project, Ballabgarh. Of these 643 had antenatal care (study group) and 439 did not receive minimum antenatal care (study group) and 439 did not receive minimum antenatal care (control group). The mean birth weights in study and control groups were 2·84 and 2·71 kg respectively and the difference was statistically not significant. The percentage of births with less than 2500 gm was 19·9 and 28·7 per cent respectively in study and control groups. This difference was highly significant. The still birth rate, first week mortality rate and perinatal mortality rate were 16·8, 12·46 and 29·0 in study group and 63·8, 48·66 and 109·3 in control group giving evidence regarding the benefit of antenatal care in reducing perinatal mortality.     

Review of the Antenatal and Postnatal Use of Steroids

Antenatal and postnatal corticosteroids play an extremely important role in the management of premature infants. The antenatal administration of steroids has been universally implemented. They have not only been shown to reduce the incidence and severity of respiratory distress syndrome (RDS), but also have an impact on the incidence of intraventricular hemorrhage (IVH), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and possibly retinopathy of prematurity (ROP) by reducing the need for supplemental oxygen due to improved lung function. The postnatal use of dexamethasone in ventilated infants has been adopted with caution, as there have been several reports of long-term neurodevelopmental complications with this therapy. Hence, changes in dosage and indications and the search for alternative therapies has emerged. Hydrocortisone appears to be a good alternative, with reassuring long-term evaluations thus far.     

Antenatal closure of the ductus arteriosus and hydrops fetalis

Antenatal closure of the ductus arteriosus has been speculated, but rarely reported, as a cause of hydrops fetalis. The purpose of this prospective autopsy study was to find the incidence of antenatal closure of the ductus arteriosus and hydrops fetalis in a high-risk obstetric population and to find associated factors that might give clues to the cause of antenatal closure of the ductus arteriosus. Antenatal closure of the ductus arteriosus had to be stringently sought by in situ examination. Fifteen stillborns with antenatal closure of the ductus arteriosus were found in 684 perinatal autopsies (2.2%), including 511 stillborns (2.9%). All 15 stillborns with antenatal closure of the ductus arteriosus also had hydrops fetalis and accounted for 35% of the 43 stillborns with hydrops fetalis. Antenatal closure of the ductus arteriosus in these 15 stillborns was not associated with maternal aspirin use but was associated with a myriad of factors, including intrauterine infection (60%), umbilical cord abnormalities (67%), and retroplacental hemorrhage (87%), that can cause hypoxic-ischemic stress.