Antenatal corticosteroids for preterm birth

Antenatal Corticosteroids for Preterm Birth Keliie Murphy, Fariba Aghajafari, and Mary Hannah

A single course o f antenatal corticosteroids is a rare example o f a treatment that yields both a health benefit and a cost savings. This article reviews the history and background o f antenatal corticosteroids, its use in~linical practice and the controversy today regarding the use o f multiple courses o f antenatal corticosteroids.

Copyright 9 2001 by W.B. Saunders Company p

reterm birth, delivery before 37 weeks' gestational age, accounts for a major and disproportionate a m o u n t of infant morbidity and mortality. 1 Today approximately 7% to 10% o f infants are born preterm. 2,s Despite advances in medical technology, the prevalence of p r e t e r m birth has actually increased. This appears to be secondary to an increase in multiple gestations, obstetric interventions, and ultrasoundbased estimates o f gestational age. 2 Fortunately, improvements have b e e n made in regards to p r e t e r m neonatal morbidity and mortality, secondary to the advances in antenatal and neonatal care such as the use of antenatal corticosteroids (ACS) and surfactant. History of Antenatal Cortieosteroids T h e effect of steroids in relationship to accelerated organ maturation in animals has b e e n known for almost 50 years. 4 Buckingham et al 5 first hypothesized that corticosteroids might have a maturation effect in the lung. However, it was Liggins 6 while studying parturition in pregnant sheep, who n o t e d that fetal lambs when exposed to ACS appeared viable at an earlier age. It was from this work that he hypothesized that antenatal steroids would accelerate fetal lung development in humans. He then went on to perform the first randomized control trial (RCT) o f ACS in 1972. 7 In this landmark study, he f o u n d that one course of corticosteroids given antenatally reduced the risk of respiratory distress syndrome (RDS) from 25.8% to 9% and also led to a decrease in neonatal mortality (15% to 3.2%, respectively). 7 Over the next 18 years, n u m e r o u s investigators repeated the work of Liggins, p e r f o r m i n g randomized controlled trials of ACS in women at risk of preterm birth. Like Liggins, many of these investigators f o u n d that ACS were associ-

ated with a decrease in RDS T M and with a decreased risk of neonatal mortality. 0,1~ O t h e r investigators r e p o r t e d no benefit. 1~17 During this time the use of ACS was a controversial and hotly debated topic in the medical literature, ls,19 Antenatal therapy was challenged with criticism as there were concerns that exposure to steroids would be detrimental leading to sequel such as maternal and fetal i m m u n e suppression. In addition, given the history o f animal studies there were concerns that steroids would alter neuronal development and force cell differentiation at the expense of cell multiplication. Others argued that the benefits o f antenatal corticosteroids outweighed the risks and argued for the universal adoption o f this practice. TM In 1990, Crowley et al20 summarized the results of 12 randomized controlled trials in a meta-analysis. This summary incorporated the results o f over 3,000 participants. It was this anal),sis that clearly showed that ACS were beneficial and highly effective in reducing rates o f RDS and neonatal mortality. 2~ Despite this convincing summary, many clinicians were still slow to adopt this antenatal therapy. Four years later, the National Institutes o f Health (NIH) held a consensus conference that reviewed the evidence and summarized the risks and benefits o f a single course of ACS in women at increased risk o f p r e t e r m birth. ~1 T h e consenFrom the Department of Obstetrics and Gynecology, University of Toronto, Mount Sinai Hospital, Ontario, Canada; and Department of Obstetrics and Gynecology, Maternal Infant and Reproductive Health Research Unit, University of Toronto, Women's CollegeHospital, Centrefor Research in Women's Health, Toronto, Canada. Address reprint requests to KeUieMurphy, MD, MSc, Department of Obstetrics and Gynecology, Mount Sinai Hospital, 600 University Ave, Toronto, Ontario MSG 1X5, Canada. Copyright 9 2001 by W.B. Saunders Company 0146-0005/01/2505-0007535.00/0 doi:l 0.1053/sper.2001.26418

Seminars in Perinatology, Vol 25, No 5 (October), 2001: pp 341-347

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sus panel concluded that ACS led to a reduction in neonatal mortality, RDS, and intraventricular h e m o r r h a g e (IVH). Furthermore they concluded that these benefits e x t e n d e d over a wide range ofgestational age ( 24 to 34 weeks) and were not limited by race or gender. 2a Indeed, today it is widely accepted that a single course o f ACS reduces morbidity and mortality in preterm infants and is indicated for most women at increased risk of p r e t e r m birth.

Pharmacology Endogenous cortisol is derived from its precursor, cholesterol, after several enymatically controlled metabolic steps. Corticosteroids act by controlling the rate of production o f various proteins. They do this by binding with cytoplasmic receptors and forming a steroid-receptor COlfi~lex. This complex then moves into the cell nucleus and binds to DNA regulating the production o f specific proteins.~ Corticosteroids have a wide variety of pharmacologicaleffects. Examples of these include the direct or indirect effects o n skeletal muscle, cardiovascular, renal, and the nervous system. Corticosteroids modulate various enzyme pathways and modulate the inflammatory response and the i m m u n e system. Additionally, corticosteroids inhibit cell division in a variety o f tissues and participate in regulation of electrolyte balance. Finally, corticosteroids influence carbohydrate, lipid, and protein metabolism. Dexamethasone and betamethasone are the preferred corticosteroids for the antenatal period. T h e reason these corticosteroids are preferred is that they readily cross the placenta in their biologically active forms, they are weak in immunosuppressive activity, they are devoid o f mineralocorticoid activity, and they have a longer duration of action than cortisol. 2s T h e bioavailability o f corticosteroids to the fetus is r e d u c e d secondary to placentai metabolism. T h e umbilical vein concentrations of betamethasone are approximately 25% to 30% o f maternal venous concentrations, m In addition, the corticosteroids do not remain in the fetal circulation for long. In one study, when the levels of betamethasone, administered prior to birth, were assayed in cord blood, the drug was undetectable 40 hours after the injection. 24

Physiology Alveolar type II pneumocytes synthesize and secrete pulmonary surfactant, a complex substance comprised of lipids and proteins. Pulmonary surfactant maintains alveolar stability and normal lung function. Its deficiency in the newb o r n infant often leads to respiratory distress syndrome. Corticosteroids are known to accelerate maturation o f developmentally regulated proteins and to stimulate cytodifferentiation in n u m e r o u s cells, including type II p n e u m o cytes. 25 In addition to increasing p r o d u c t i o n o f surfactant, corticosteroids increase lung compliance and maximal lung volume. 26 Finally, corticosteroid treatment appears to reduce protein leak from the pulmonary vasculature into the airspace and appears to accelerate clearance o f lung liquid before delivery. ~7 These effects represent precocious maturation and are essential in the transition to air breathing. 27 It is unknown whether the beneficial effects of ACS on surfacrant and other proteins are reversible. If the effects are reversible, it is unknown whether the levels o f surfactant and these proteins return to p r e t r e a t m e n t levels or to new higher levels. At present, experimental evidence suggests that the induction o f surfactant in fetal lung may be reversible. 2s,29 Transcription rates o f surfactant proteins have been f o u n d to be significantly reduced, 4 hours after the removal o f cortisol, in h u m a n fetal lung culturesY 9 Risks and Benefits of a Single Course of Antenatal Corticosteroids T h e greatest benefit of a single course of ACS for foetuses at increased risk of preterm birth is a reduction in RDS. In the most recent Cochrane meta-analysis, the odds ratio for an effect o f ACS on RDS was 0.53 (95% CI: 0.44, 0.63)20 ACS were also f o u n d to significantly reduce the risks o f IVH, neonatal mortality, and the n e e d for surfactant therapy. Infants exposed to ACS have also b e e n f o u n d to have an improved circulatory stability, requiring reduced amounts of oxygen and ventilatory support, sl To date, follow-up studies of infants enrolled in RCTs have not shown any long-term adverse effects after a single course of ACS. ~2-~4 Children were followed-up for 20 years in 1 study. T h e r e were no significant differences between the children that received a single course o f ACS, as c o m p a r e d to

Antenatal Corticosteroidsfor Preterm Birth

those who did not, in terms of growth, medical, or psychological variables, as T h e potential adverse maternal side effects o f a single course o f ACS include an increased risk o f infection such as chorioamnionitis and endometritis. However, in Crowley's meta-analysis, the frequency o f maternal infection was similar between women x~ho received and those who did n o t receive ACS. a~ In addition, a meta-analysis, which incorporated data from over 1,400 w o m e n with preterm prelabor rupture o f m e m b r a n e s (PPROM), f o u n d that a single course of ACS was associated with a decrease in RDS (RR 0.56:0.460.70 CI), IVH (RR 0.47:0.31-0.70 CI), and necrotizing enterocolitis (RR 0.21:0.05-0.82 CI).35 Although the effectiveness of one course of ACS (greater benefit than risk for those treated) has been proven, there is uncertainty as to how long the treatment continues to be effective if the woman remains undelivered 7 or m o r e days after the initial dose. When the Liggins trial was r e p o r t e d in 1972, they reported the risk o f RDS a m o n g liveborn infants after u n p l a n n e d premature labor in 5 categories, those b o r n at < 2 days, 2-<7 days and -----7days. They did not r e p o r t the effects o f ACS for those born at 7 to 14 days or at o t h e r intervals o f time after the initial dose. T h e y f o u n d that the risk o f RDS was significantly r e d u c e d after treatment with ACS (versus control) a m o n g foetuses born between 2 days and less than 7 days after trial entry (3.6% v 33.3%, P = .03), but the effect on RDS was not statistically significant after treatment with ACS (versus control) if foetuses were born 7 or m o r e days after trial entry (2.2% v 9.4%, P .05)Y T h e Collaborative Group on Antenatal Steroid Therapy also r e p o r t e d their results for singleton infants in this way. They found the risk o f RDS to be r e d u c e d with ACS (versus placebo), if delivery o c c u r r e d 24 hours to 7 days after trial entry (9.3% v 20.1%), and if delivery occurred > 7 days after trial entry (6.0% v 10.5%).36 The question has arisen, therefore, as to whether the effectiveness of the ACS is lost or reduced if the woman remains undelivered 7 days after treatment. Because of this, and because the risk o f RDS and o t h e r complications of prematurity are high for foetuses b o r n very preterm, some clinicians have suggested that weekly courses o f ACS should be given to women who are at increased risk o f preterm birth and remain undelivered 7 or m o r e days after the initial dose. s7 In some

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medical centers, this approach has b e c o m e routine despite the fact that multiple courses o f ACS have not been shown to be effective in welldesigned RCTs. In a recent survey of Australian obstetricians, 85% of obstetricians indicated that they prescribe multiple courses o f ACS for women who remain at increased risk o f p r e t e r m birth, ss In a survey in 1996 of maternal fetal medicine specialists in the United States, 96% stated that they would give m o r e than 1 course of ACS and 58% would give 6 or more courses, s9 In the United Kingdom in 1999, 98% of obstetricians indicated that they prescribe multiple courses o f antenatal corticosteroids. 40 Risks and Benefits o f Multiple Courses o f ACS in Animals T h e basis of ACS therapy originated from animal studies. Likewise, a great deal of literature regarding the risks and benefits of multiple courses of antenatal corticosteroids comes from animal work. T o date, at least 19 randomized controlled trials in animals comparing a single dose o f ACS with multiple doses have been published. Lung. Eight trials have assessed the effects of multiple doses o f ACS o n lung function. These studies have b e e n p e r f o r m e d in sheep, monkeys, rabbits, and mice. Briefly, all o f these studies have reported improved lung function after exposure to multiple doses o f ACS. T h e studies in sheep f o u n d that multiple doses of ACS were associated with improved lung compliance, imp r o v e m e n t in ventilatory efficiency index, an increase in lung volume, 41 and an increase in the production and secretion o f surfactant components. 42,4a Finally, Walther et a144 randomized p r e g n a n t sheep to single versus multiple doses of ACS and f o u n d that multiple dose exposure was associated with an increase in antioxident enzymes (the primary defense against free radicals) and a decrease in free radicals. This is important as free radicals mediate oxygen-induced cellular damage in immature lung tissue. Monkeys exposed to multiple doses of ACS have been shown to have higher levels o f phosphatidylcholine, surfactant phosphatidylcholine, and a higher ratio of surfactant-phosphatidylcholine to phosphatidylcholine c o m p a r e d with those who received 1 dose. 45 Studies in rabbits exposed to multiple doses o f ACS have shown an

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increase in surfactant proteins and an improvem e n t in ventilation. 46 Finally, alveolar developm e n t and breathing scores were f o u n d to be greater in mice exposed to multiple doses o f A C S , 47

Nervous system. Six animal RCTs have looked at the effects o f repeated doses of ACS on nervous system function or growth. These studies have been p e r f o r m e d in sheep, monkeys, and mice. Trials in sheep exposed to multiple doses of ACS have shown alterations in optic nerve myleninat i o n , 48'49 a decrease in eye diameter, and retinal thickening. 5~ Quinlivan et a151 has also shown that multiple doses o f ACS in sheep lead to alterations in sciatic nerve development. O t h e r studies have shown an association o f multiple doses o f ACS and a reduction in brain volume. 52 In Monkeys exposed to multiple doses o f ACS, Uno et alsa showed an association with neuronal degeneration and a decreased n u m b e r o f neurons in the hippocampus. A behavioral study in mice did not show any differences in responses to motivation/anxiety testing when exposed to a single versus multiple doses o f ACS. 54 Growth. Twelve trials have looked at the effect of repeated doses o f ACS on fetal growth. All o f these studies have r e p o r t e d an association o f multiple doses of ACS and a decrease in birth or organ weight. Trials have been p e r f o r m e d in s h e e p , 41,42,48,55,56,57 monkeys, 45 rabbits, 46,5s and mice. 59 Risks and Benefits o f Multiple Courses o f ACS in H u m a n s

T h e r e is insufficient data available from completed well-designed RCTs as to the benefits and risks of multiple courses o f ACS in humans. T h e data from RCTs as o f January 2001 include Guinn's final analysis o f data from 502 women randomized to single versus multiple courses o f antenatal corticosteroids. 6~ This work, although underpowered, is perhaps the best evidence to date of the effects o f multiple versus single courses o f antenatal corticosteroids. This study showed no difference in the primary outcome (a composite o f severe RDS, b r o n c h o p u l m o n a r y dysplasia, severe IVH, periventricular leukomalacia, neonatal sepsis, necrotizing enterocolitis or neonatal death) between the infants who received single versus multiple courses o f ACS. 6~

A n o t h e r small RCT (N=146) (comparing multiple courses of ACS versus placebo) f o u n d that ACS was associated with a statistically significant reduction in RDS and death, but over 50% o f randomized foetuses were excluded from the analysis, and the effect f o u n d may have b e e n the result of the initial versus the subsequent c o u r s e s . 61

Several observational retrospective studies have reported on the risks and benefits o f multiple versus single courses of ACS. Many suggest that multiple courses o f ACS c o m p a r e d to a single course are beneficial and decrease the risk o f RDS and pulmonary disease. 6~-64A n o t h e r retrospective analysis has reported a significant decrease in oxygen use in infants who received multiple courses of ACS. 65 Given the known benefits o f a single course ofACS (ie, decreased risk of RDS, IVH, and neonatal mortality), it follows that multiple courses of ACS could continue to benefit an infant if the pregnancy is at increased risk o f p r e t e r m birth and remains undelivered 7 or more days after the initial dose. However, other retrospective observational studies have reported on the adverse effects o f multiple (versus single) courses o f ACS. These effects include a reduction in birth weight 66,6v and head circumference. 6a,6v A recent prospective study reported an increased risk o f neonatal i n f e c t i o n in women with p r e t e r m p r e m a t u r e rupture o f membranes following multiple courses o f ACS. ~ Although o t h e r investigators have not f o u n d an increase in neonatal infection or disturbances in growth.62 O t h e r adverse effects r e p o r t e d include I case o f neonatal cushingold syndrome after 7 courses of ACS, and hyperactive behavior in children at 3 years o f age.69,70 A ~ y e a r follow-up study o f children who received single versus multiple courses o f ACS showed n o difference in growth or disabilities between the 2 groups. 67 Another, 2- to 6-year follow-up study r e p o r t e d n o adverse effects on blood pressure or growth. 71 A recent meta-analysis o f these retrospective studies reported a decreased risk o f RDS and patent ductus arteriosus after multiple courses of ACS. In this meta-analysis, multiple courses o f ACS did not have any effect on neonatal sepsis, mortality, IVH, b r o n c h o p u l m o n a r y dysplasia, necrotizing enterocolitis or birth weight less than the 10%. v~ T h e majority of studies regarding the risks

Antenatal Corticosteroidsfor Preterm Birth

and benefits in humans are retrospective in design. T h e biggest limitation with these studies is selection bias. Essentially, women who received multiple courses o f ACS were different from those who received a single course. W o m e n who received multiple courses either presented at risk of p r e t e r m birth earlier in gestation and thus had a hi~her likelihood o f an adverse event a n d / o r delivered later, thus had the opportunity to receive multiple courses of ACS, and may have had a lower likelihood o f an adverse event. In addition, most o f the observation studies did not control for confounding variables s u c h as multiple pregnancy, p r e t e r m prelabor rupture of membranes and preeclampsia. It is impossible to assess the true effects of multiple courses of ACS by reviewing the results of observational studies secondary to selection bias and confounding variables. Randomized controlled triMs are n e e d e d to assess the risks and benefits o f a single versus multiple courses o f ACS.

Conclusion It is clear that a single course of ACS has very substantial and immediate benefits for p r e t e r m infants and are indicated in most women at risk o f p r e t e r m birth before 34 weeks' gestation. However, the evidence in regards to risks and benefits from multiple courses of ACS is unclear. Therefore, the practice of administering multiple courses of ACS should be addressed in large multicenter randomized trials with an emphasis on assessing long-term effects on growth and neurodevelopment. Several such studies are planned (United Kingdom) or are in progress (Australia, United States, and Canada). T o reiterate the conclusions from the NIH Consensus Conference on multiple courses o f ACS: there is insufficient knowledge regarding the risks and benefits o f multiple courses o f ACS, and therefore, the practice of giving multiple courses o f ACS should be reserved only for women enrolled in randomized controlled trials. However, the current prospective randomized trials are essential and should continue in o r d e r to answer this important question. 73

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