Scholarly article on topic 'Effects of Antenatal Corticosteroids in Preterm Delivery'

Effects of Antenatal Corticosteroids in Preterm Delivery Academic research paper on "Clinical medicine"

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{"respiratory distress syndrome" / "intraventricular hemorrhage" / "periventricular leukomalacia" / "necrotizing enterocolitis" / betamethasone / dexamethasone}

Abstract of research paper on Clinical medicine, author of scientific article — Kuo-Gon Wang, Chen-Yu Chen, Chie-Pein Chen

Summary Antenatal corticosteroid administration is one of the most effective methods to improve perinatal outcomes. It reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia and necrotizing enterocolitis in preterm neonates. Antenatal corticosteroids are also effective in treating maternal hemolysis, elevated liver enzymes and low platelet count syndrome. However, complications in neonates and mothers may occur when antenatal corticosteroids are given, including infection, sepsis and maternal pulmonary edema. The National Institutes of Health Consensus Development Conference recommends treatment regimens of either two 12 mg doses of betamethasone given intramuscularly 24 hours apart or four 6 mg doses of dexamethasone given intramuscularly 12 hours apart between 24 and 34 weeks of gestation in pregnancies at risk for preterm delivery. The benefits are most apparent when the corticosteroids are administered between 24 hours and 7 days before delivery. In principle, antenatal steroid therapy should not be routinely repeated in patients with preterm labor. For preterm premature rupture of membranes at less than 30–32 weeks of gestation, antenatal corticosteroids are also suggested as long as there is no evidence of infection.

Academic research paper on topic "Effects of Antenatal Corticosteroids in Preterm Delivery"

REVIEW ARTICLE

Effects of Antenatal Corticosteroids in Preterm Delivery

Kuo-Gon Wang1,2*, Chen-Yu Chen1, Chie-Pein Chen1 1 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, and 2Department of Obstetrics and Gynecology, Taipei Medical University, Taipei, Taiwan.

SUMMARY

Antenatal corticosteroid administration is one of the most effective methods to improve perinatal outcomes. It reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia and necrotizing enterocolitis in preterm neonates. Antenatal corticosteroids are also effective in treating maternal hemolysis, elevated liver enzymes and low platelet count syndrome. However, complications in neonates and mothers may occur when antenatal corticosteroids are given, including infection, sepsis and maternal pulmonary edema. The National Institutes ofHealth Consensus Development Conference recommends treatment regimens of either two 12 mg doses of betamethasone given intramuscularly 24 hours apart or four 6 mg doses of dexamethasone given intramuscularly 12 hours apart between 24 and 34 weeks of gestation in pregnancies at risk for preterm delivery. The benefits are most apparent when the corticosteroids are administered between 24 hours and 7 days before delivery. In principle, antenatal steroid therapy should not be routinely repeated in patients with preterm labor. For preterm premature rupture of membranes at less than 30-32 weeks of gestation, antenatal corticosteroids are also suggested as long as there is no evidence of infection. [TaiwaneseJ Obstet Gynecol 2004;43(4):193-198]

Key Words: respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, betamethasone, dexamethasone

Introduction

In 1969, Liggins found that premature lambs given glucocorticoids in utero survived longer than untreated control lambs [1]. Three years later, Liggins and Howie first used antenatal corticosteroid treatment in pregnant women to prevent respiratory distress syndrome (RDS) in preterm neonates, resulting in decreased neonatal mortality [2]. Subsequently, serial studies have confirmed the effectiveness of this therapy [3-8]. Additionally, many randomized or controlled trials have demonstrated

* Correspondence to: Dr. Kuo-Gon Wang, Department of Obstetrics

and Gynecology, Mackay Memorial Hospital, 92, Section 2,

Chung-Shan North Road, Taipei, Taiwan.

E-mail: aikuo7@ms15.hinet.net

Received: May 25, 2004

Revised: May 26, 2004

Accepted: May 28, 2004

that antenatal corticosteroids reduce the risk of RDS, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) and necrotizing enterocolitis (NEC) [9-11]. However, complications, such as infection, sepsis and maternal pulmonary edema, have been noted in both neonates and mothers [12-14]. We reviewed articles published from the 1970s to 2004 and discuss the benefits and risks of antenatal corticosteroids.

Betamethasone vs Dexamethasone

Betamethasone and dexamethasone have generally been the preferred corticosteroids because of their beneficial effect on fetal organ development. These agents have relatively good placental transfer, a long half-life and duration of activity, identical biologic effects, little min-eralocorticoid activity, and relatively weak immunosuppressive activity [12]. They are almost identical in

structure, differing only in the a versus P position of the methyl group at position 16. In 1994, the National Institutes of Health (NIH) recommended either two 12 mg doses of betamethasone given intramuscularly 24 hours apart or four 6 mg doses of dexamethasone given intramuscularly 12 hours apart between 24 and 34 weeks of gestation [12]. Rayburn et al studied beta-methasone and dexamethasone in pregnant mice and found subtle differences in memory and behavior in the offspring. They concluded that betamethasone was better than dexamethasone in terms of neurobehavioral development in mice [15]. Baud et al published a retrospective study of 883 infants with gestational ages between 24 and 31 weeks, and found that betametha-sone was associated with a lower risk of PVL than dexamethasone [16]. Whitelaw and Thoresen reviewed the literature and recommended betamethasone rather than dexamethasone for antenatal corticosteroid therapy [17]. However, several prospective randomized trials have revealed that betamethasone has a greater propensity than dexamethasone to suppress fetal heart rate and biophysical activity [18-20]. The suppression is temporary, but awareness of this particular drug-induced effect is important so that it is not interpreted as fetal distress requiring immediate delivery.

Fetal Effects

Respiratory distress syndrome

Liggins and Howie performed a randomized controlled study in 282 mothers and found that betamethasone 12 mg intramuscularly in two doses, 24 hours apart, prevented RDS in their preterm neonates [2]. Babies born before 34 weeks had a significant reduction in RDS and neonatal mortality if birth was delayed for at least 24 hours or up to 7 days after completion of the course of betamethasone, as substantiated by a number of other studies [3-8].

Ballard et al compared the outcome in 114 infants with birth weights between 750 and 1,750 g whose mothers received antenatal betamethasone therapy with that in 138 infants born to untreated mothers [4]. The incidence of RDS after betamethasone was 37.7% compared with 50.7% without treatment. Doran et al performed a double-blind controlled study of antenatal betamethasone treatment in 137 patients from 24 to 34 weeks of gestation [6]. The incidence of RDS was less in the treated group (5%) than in the control group (17%), and neonatal mortality was lower in the treated group (5%) than in the control group (18%). Young et al carried out a prospective trial of intravenous dexamethasone for prevention ofneonatal RDS in 112 moth-

ers compared with 188 untreated controls [7]. In neo-nates born at 28 to 33 weeks of gestation, the treatment group had half the perinatal mortality and one-fourth the incidence of severe RDS seen in the control group.

Crowley et al analyzed data from 12 controlled trials involving over 3,000 women [21]. They demonstrated that antenatal corticosteroid administration reduced the risk of neonatal RDS by 50%, and this benefit was most obvious when the interval from corticosteroid treatment to delivery was between 24 hours and 7 days. Maher et al retrospectively reviewed a group of very preterm infants born to 432 women who delivered at 26 to 31 weeks [22]. Of these mothers, 67 had received antenatal betamethasone and 365 had not. When betamethasone was administered at least 2 days before delivery, there was a lower incidence of RDS in both the 26-28-week group (53.9% vs 86.5%) and the 29-31-week group (25.0% vs 59.1%), compared with the untreated group. In a regression analysis of neonates born between 26 and 31 weeks, the odds ratio (OR) for RDS after betamethasone treatment was 0.20 (confidence interval [CI], 0.10 to 0.42).

The mechanism by which treatment is thought to reduce the frequency ofRDS is the induction of enzymes controlling biosynthesis of surfactant in the fetal lung. Effects of antenatal corticosteroids on the developing lung include increased tissue and alveolar surfactants, increased compliance and maximal lung volume, decreased vascular permeability, more mature parenchymal structure, enhanced clearance of lung water, enhanced response to surfactant treatment and improved respiratory function [23].

Intraventricular hemorrhage

In 1986, Morales et al carried out a prospective, blinded, randomized study of antepartum dexamethasone administration in 250 women between 28 and 33 weeks' gestation who had preterm premature rupture of membranes (PPROM) [24]. The dexamethasone-treated group had a lower incidence of IVH. More recently, O'Shea et al collected data on 201 neonates with very low birth weights, and found that maternal treatment with betamethasone was associated with a decreased incidence of IVH [25]. During the same period, Garite et al performed a double-blind clinical trial of antenatal betamethasone treatment in mothers with intact membranes and threatened premature delivery between 24 and 28 weeks' gestation [26]. The treatment group of 36 mothers received two 12 mg doses of betametha-sone, 24 hours apart, while 41 mothers received placebo. The incidence of grade 3 (blood acutely distending the lateral ventricles) and grade 4 IVH (blood within the ventricular system and parenchyma) was lower in the

betamethasone-treated group (betamethasone vs placebo, 1/31 vs 9/36; p = 0.01). In 2003, Linder et al studied a cohort of 641 preterm neonates with a birth weight of less than 1,500 g, ofwhom 36 had grade 3 or 4 IVH [27]. Risk factors for IVH in this group included early sepsis and lack of antenatal corticosteroid administration.

Many observers believe that IVH is a consequence of increased cerebral blood flow to the delicate germinal matrix capillary network. Corticosteroids induce perinatal maturation of the germinal matrix microvascula-ture, making them more resistant to rupture, thus decreasing the risk of IVH [26,28].

Periventricular leukomalacia

PVL is the most frequent cause of cerebral palsy in children who are born prematurely and is considered a sonographic marker for cerebral palsy [29,30]. Unlike IVH, little is known about the relationship between antenatal glucocorticoids and the incidence of PVL. Baud et al performed a retrospective analysis of 883 infants born between 24 and 31 weeks of gestation [16]. In this series, 361 mothers received antenatal betamethasone, 165 mothers received dexamethasone and 357 mothers did not receive any glucocorticoid. The incidence of PVL was 4.4% in neonates in the betamethasone group, 11.0% in the dexamethasone group and 8.4% in the no-treatment group. Betamethasone was thus associated with a lower incidence ofPVL compared with no glucocorticoid therapy (OR, 0.5; 95% CI, 0.2-0.9) and dexamethasone (OR, 0.3; 95% CI, 0.1-0.7).

Canterino et al carried out another retrospective cohort study that included 1,161 neonates born between 24 and 34 weeks with birth weights of 500-1,750 g [11]. They found that neonates of mothers treated with antenatal betamethasone had a 56% lower risk of PVL with IVH (OR, 0.44; 95% CI, 0.25-0.77) and a 58% lower risk of isolated PVL (OR, 0.42; 95% CI, 0.200.88). The physiologic effects of antenatal corticosteroid administration include accelerated cytodifferentiation, greater maturity of cerebrovascular endothelial cells and autoregulation of cerebral perfusion, and increased activity of antioxidant enzymes, which lessens the risk of neurologic cell damage [11].

Necrotizing enterocolitis

The pathogenesis ofNEC is not well understood. Factors thought to increase the risk of intestinal injury include prematurity, enteral feeding, intestinal ischemia and bacterial colonization [31]. Results vary in studies examining the effect of antenatal steroid administration on the incidence of NEC. In 1984, Bauer et al reported a significantly decreased incidence of NEC (p = 0.002) in a large multicenter, randomized, blinded trial of ante-

natal corticosteroids, which included 696 mothers and their 745 infants [32]. They concluded that antenatal corticosteroid therapy appeared to accelerate intestinal maturation. More recently, Halac et al performed a study of 466 women in premature labor given either placebo (n = 256) or betamethasone (n = 210) [33]. The incidence ofNEC was significantly lower in the betamethasone group. However, Uauy et al and Wells et al were not able to demonstrate a decreased risk for NEC after antenatal steroid therapy [34,35].

Neonatal infection and sepsis

In the systematic review of 3,000 mothers by Crowley et al, the incidence of neonatal infection was not significantly higher in the corticosteroid-treated group than in the control group [21]. Vermillion et al prospectively studied pregnancies where infants were delivered between 24 and 34 weeks' gestation after antenatal betamethasone administration [13]. A total of 453 mothers were included in this study, of whom 267 received a single course of betamethasone (two 12 mg doses in a 24-hour interval) and 186 received multiple courses of betamethasone (the same initial single regimen and then additional doses before delivery, either as a single rescue dose within 14 days of the initial course or as a weekly prophylactic regimen). They concluded that multiple courses of betamethasone in women delivering before 34 weeks of gestation increased the risk of early-onset neonatal sepsis (OR, 5.00; 95% CI, 1.323.2) and sepsis-related neonatal death (OR, 2.92; 95% CI, 1.3-6.9).

Neonatal mortality

Given the benefits of antenatal corticosteroid therapy in reducing the incidence of RDS, IVH, PVL and NEC, we would expect to see a significant decrease in neonatal mortality. This is borne out by a number of studies. RDS is the most acute problem in the very premature infant and, together with IVH, is a major risk factor for neonatal death. In the overview by Crowley et al, the incidence of early neonatal death was significantly lower in the corticosteroid-treated group than in the control group (OR, 0.59; 95% CI, 0.47-0.75) [21]. More recently, Crowley performed a meta-analysis of randomized trials of antenatal corticosteroid therapy published between 1972 and 1994, and found that neonatal mortality remains substantially lower in infants of corticosteroid-treated mothers (OR, 0.60; 95% CI, 0.48-0.76) [10]. Maher et al, in their study of infants born between 26 and 31 weeks, found that the OR for neonatal mortality in these very preterm infants after antenatal betamethasone was 0.14 (95% CI, 0.021.09) [22].

Long-term adverse effects

Several studies since the 1970s have followed the development of infants and children for as long as 12 years and have shown no adverse effects of antenatal corticosteroids on motor skills, language, cognition, memory, concentration or scholastic achievement [12]. Schaap et al performed a case-control study to evaluate the effects of antenatal corticosteroid administration on mortality and long-term morbidity in early preterm (26-32 weeks' gestation), growth-restricted neonates [36]. Both the corticosteroid-treated and control groups consisted of 62 neonates. Children in the corticosteroid-treated group were more likely to survive with no disability or handicap at 2 years of age (OR, 3.2; 95% CI, 1.111.2). By school age, there were no detectable differences in behavior, but physical growth in the steroid-treated group was significantly reduced (OR, 5.1; 95% CI, 1.423.8).

Maternal Effects Maternal pulmonary edema

An increased risk of maternal pulmonary edema has been reported when antenatal corticosteroids are administered in combination with tocolytic agents, with a reported incidence during co-administration of steroids and betamimetics of about 5% [14]. Two cases of pulmonary edema have been reported in women who had received both corticosteroids and magnesium sulfate, an incidence in that series of 1.6% [37]. It is good to remember that fluid overload, multiple gestations and underlying heart disease are other significant precipitating factors for maternal pulmonary edema. This complication has not been reported when antenatal corticosteroids are administered alone.

Maternal infection

The risk of maternal infection may be increased when antenatal corticosteroids are used in PPROM [12,38]. In the meta-analysis by Crowley, the OR for maternal infection in this situation was 1.15 (95% CI, 0.841.57) [10]. In the study by Vermillion et al comparing single versus multiple courses of betamethasone, the latter was significantly associated with chorioamnionitis (OR, 9.96; 95% CI, 2.1-64.6) and endometritis (OR, 3.61; 95% CI, 1.7-8.1) [13].

HELLP syndrome

HELLP syndrome (hemolysis, elevated liver enzymes and low platelet counts) is a well-recognized complication of severe pre-eclampsia and eclampsia, and is associated with increased maternal and perinatal mortality. Dexa-

methasone effectively ameliorates HELLP in antepartum patients and accelerates postpartum recovery [39,40]. Isler et al demonstrated that intravenously administered dexamethasone appears to be more effective than intramuscularly administered betamethasone for antepartum or postpartum HELLP syndrome [41,42]. It has been hypothesized that corticosteroids are beneficial in this entity because of their effects on the systemic microvasculature, particularly in the hepatic and renal vascular beds. Nevertheless, further investigation appears to be warranted to determine the optimal corticosteroid dose, timing of treatment and route of administration.

Single vs Multiple Courses of Corticosteroids

Many studies have compared the benefits and risks of a single course versus multiple courses of antenatal corticosteroid administration, with most indicating a greater incidence of short- or long-term adverse effects with multiple courses. These may include neonatal infection and death, maternal and fetal adrenal suppression, maternal infection, impaired glucose tolerance, osteoporosis, reduction of neonatal birth weight and head circumference, and possibly an increased incidence of neonatal chronic lung disease [13,43-45]. Moreover, no obvious reduction in RDS, IVH, PVL, NEC and neonatal sepsis has been demonstrated in women treated with repeated courses of corticosteroid therapy [38, 44,46]. Nevertheless, several other studies have reached opposite conclusions, finding no significant adverse effects on neonatal birth weight, head circumference, or neonatal and maternal infection after multiple courses of corticosteroids [47,48].

Based on the available evidence, the NIH and Goldenberg and Wright have concluded that current data are insufficient to support routine use of repeated or rescue courses of antenatal corticosteroids [49,50]. They recommend further prospective randomized clinical trials to resolve this question. Nevertheless, many obstetricians are concerned when the risk for premature delivery persists after one course of steroids has already been given, especially if it was given long before 34 weeks' gestation. Is it safe to forgo further treatment despite the ongoing risk? Caughey and Parer used decision analysis to develop a strategy for pregnancies at risk for preterm delivery between 24 and 34 weeks [51]. Based on their model, if there is still a potential risk of preterm delivery subsequent to the first course of corticosteroids, a second course may be administered 2 weeks later, but no more than two courses should be given. They also emphasized the need for randomized clinical trials to assess this strategy.

Conclusions

The benefits of antenatal corticosteroids in reducing morbidity and mortality in preterm neonates are clear and generally outweigh the risks associated with this therapy. As the benefits are most obvious when the treatment is given within 1-7 days before delivery, the main question remaining to be answered is what to do if steroids have already been given but delivery is delayed beyond a week after that. At this point, the evidence is inadequate to give a firm answer, so the decision must be based on theoretical considerations. It is hoped that prospective clinical trials will eventually provide adequate information to answer this question.

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