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Re: 23 weeks promFrom: Efrain Ramirez (eramirezt@coqui.net)Mon Feb 19 06:19:12 2007
Editorial: Antenatal corticosteroids: Is early and often too much? Oct 1, 2006 By: Charles J. Lockwood, MD Contemporary OB/GYN Charles J. Lockwood, MD If you feel whipsawed about when and how often to treat patients at risk for prematurity with antenatal corticosteroids (ACS), you're not alone. Let's review the data and then I'll give you my recommendations for a practical, evidence-based approach. Early studies Use of ACS really began with a chance finding by Professor Sir Graham Liggins of the University of Auckland, New Zealand, nearly 40 years ago.1 His observation—in ewes—that exogenous corticosteroids induced parturition and also improved postnatal survival by enhancing fetal lung maturation led to the first randomized controlled trial (RCT) of ACS in humans.1 Four years later, Liggins and Howie found a lower rate of respiratory distress syndrome (RDS) in premature infants born to mothers who had been given ACS versus placebo (9% vs. 25.8%).2 The infants who benefited the most were those delivered 2 to 7 days after therapy (3.6% vs. 33.3%) and at 26 to 32 weeks' gestation (11.8% vs. 69.6%). TABLE 1 Clinical benefits of a single course of ACS* By the mid-1990s, the Cochrane Database listed 18 well-designed RCTs examining the efficacy of treatment of women at risk for preterm delivery (PTD) with a single course of ACS.3 Meta-analysis of these studies showed that the therapy reduced RDS in all premature infants and in the subset delivered before 30 weeks (Table 1). Infants delivered within 1 to 7 days of treatment, whether male or female, also benefited. In addition, a single course of ACS reduced risk of neonatal death and intraventricular hemorrhage (IVH). And just as important, the therapy was associated with no major maternal or fetal risks. NIH takes the lead Despite ACS's impressive benefits, obstetricians initially were slow to adopt the approach. To encourage use of the drugs in at-risk pregnancies, the National Institutes of Health (NIH) sponsored a Consensus Conference on the effect of ACS on perinatal outcomes in 1994.4 The conclusion: ACS reduced neonatal mortality, RDS, and IVH, and the benefits extended from 24 to 34 weeks. The panel also posited that while the greatest benefits accrued after 24 hours of treatment, therapy for less than 24 hours might improve outcomes. The panel recommended that: ACS be considered in all 24- to 34-week fetuses at risk of PTD, regardless of fetal race or gender or availability of surfactant therapy, as long as there were no contraindications to the therapy. Treatment consist of two, 12-mg doses of betamethasone IM 24 hours apart, or four 6-mg doses of dexamethasone IM 12 hours apart. Optimal benefits should be considered to begin 24 hours after initiation of therapy and to last 7 days. ACS should be used in cases of preterm premature rupture of membranes (pPROM) at less than 30 to 32 weeks with no clinical chorioamnionitis, because of the high risk of IVH. Repeat courses take hold The NIH panel's recommendation had the desired effect. Use of ACS to enhance fetal lung maturity began to skyrocket.5,6 Indeed, concern that the treatment's beneficial effects lasted only 7 days led more and more clinicians to repeat courses weekly in at-risk patients. Some clinicians even began giving ACS prophylactically to patients at particularly high risk, such as women with multifetal gestations. And then, at the height of this "therapeutic exuberance," reports began to surface in the pediatric literature of a significantly increased incidence of major neurodevelopmental abnormalities, including cerebral palsy (CP), in infants given dexamethasone to prevent chronic lung disease (OR of 4.6; 95% CI; 1.3–21.7).7 Several animal studies also suggested that repeat treatment with ACS was harmful to cerebral myelination, lung growth and architecture, retinal development, renal glomerular number, pancreatic islet cell numbers, and hypothalamic-pituitary-axis functioning. Even more ominous were findings from French and associates' 3-year follow-up study of children exposed to ACS; multivariate analysis indicated that repeated treatment reduced birthweight by up to 9% and head circumference by up to 4%.8 Alarmed by the prospect that repeated ACS courses might do harm, the NIH held a second consensus conference in 2000. That panel concluded that there was unequivocal support in the literature for use and efficacy of a single course of ACS given to at-risk women at the dosage and intervals specified in 1994, but those data were insufficient to support routine use of repeat or rescue treatment.9 Soon thereafter, Guinn and colleagues published results of the first RCT of single versus weekly ACS in women at risk for PTD.10 They found that weekly ACS decreased the latency period between initial therapy and delivery but had no effect on a composite index of perinatal morbidity. Interestingly, the authors found that in infants delivered before 28 weeks, weekly ACS reduced the prevalence of severe RDS by 27% and lowered the occurrence of composite perinatal morbidity by 20% (P<0.03). Similar findings were noted in Lee and colleagues' secondary analysis of the same data in patients with pPROM.11 That study showed that in infants delivered before 28 weeks, weekly ACS decreased the occurrence of severe RDS from 100% to 26.5% (P<0.001)! Taken together, these findings suggested that repeat ACS courses might be beneficial in a subset of fetuses born before 28 weeks. Even more recently, Wapner and associates reported the results of a clinical trial of women at risk for premature birth between 23 and 32 weeks who received one course of steroids 7 to 10 days earlier and were then randomized to receive weekly betamethasone courses versus placebo. They observed that although repeated doses of steroids significantly reduced the need for neonatal surfactant, mechanical ventilation and the occurrence of pneumothoraces, when compared to placebo, repeated courses failed to significantly reduce a composite index of morbidity (a combination of acute and chronic lung disease, brain injury, and perinatal death) (9.1% vs. 8.0%, respectively, RR 0.88 (95% CI; 0.49–1.57). Moreover, while there was no significant difference in mean birthweight or head circumference between the groups, the repeated course group had more neonates weighing less than the 10th percentile (23.7% vs. 15.3%, P=0.02) and significant weight reductions occurred for the group receiving four or more courses.12 Balancing benefit and risk The saga came full circle 3 months ago, with Crowther and colleagues' large RCT of single versus repeat courses of ACS.13 Their study was unique in that "repeat courses" of steroids consisted of weekly injection of a single, 12-mg dose of betamethasone, instead of the usual two doses. Fewer infants exposed to repeat ACS had RDS (RR 0.82; 95% CI; 0.71–0.95) and severe lung disease (0.60; 95% CI; 0.46–0.79). Moreover, the repeat ACS group had a lower incidence of patent ductus arteriosis, needed less oxygen and surfactant, and were off mechanical ventilation sooner (P=0.01). There were no differences between the two groups in mean birthweight, length, or head circumference. Interestingly, French and associates' 6-year follow-up data of their ACS-exposed children showed that more ACS courses were associated with a lower rate of CP (OR of 0.31–0.35; 95% CI; 0.16–0.75), but that three or more courses were linked to increased rates of aggressive/destructive, distractible, and hyperkinetic behavior.14 These generally salutary effects must be balanced against the results of Dalziel and colleagues' 30-year follow-up of infants exposed to ACS, which showed that exposed individuals had higher plasma insulin concentrations after a 75-g oral glucose tolerance test.15 This finding suggests that ACS may act via the Barker hypothesis mechanism—in utero stress leads to adult disease—to increase insulin resistance in adulthood. Furthermore, Thorp and associates used multiple regression analysis to examine outcomes in nearly 15,000 premature infants and noted that ACS exposure was associated with a 63-g reduction in birthweight and a 3.1-mm reduction in head circumference.16 Those findings again suggest a potential long-term risk of Barker sequelae from ACS exposure. Putting the data into practice Where does this deluge of complex, seemingly contradictory data lead us? During fetal development, insulin and corticosteroids play a Yin and Yang role. Insulin enhances cell hyperplasia and hypertrophy to promote growth, but at the cost of delaying organ maturation. That's why infants born to mothers with poorly controlled diabetes are macrosomic but have immature endocrine organs and lung function. Corticosteroids, in contrast, augment organ maturation at the cost of impaired growth and premature organ differentiation. That helps account for the accelerated lung and endocrine maturity in highly stressed, growth-restricted fetuses, and also for their lagging biometry, neurodevelopmetal impairment, and accelerated incidence of cardiovascular disease and diabetes later in life. It's not surprising, then, that ACS would enhance lung maturity and reduce risk of IVH and, potentially, CP but be associated with very mild growth reduction and Barker sequelae. Clearly, repeated doses of ACS are likely to enhance both these salutary and harmful effects. Remote from term, however, the theoretical risks of a repeat ACS course appear to be outweighed by the benefits of a reduced occurrence of severe RDS and IVH. Balancing benefits and risks is always our responsibility as clinicians, and in the area of ACS therapy, this is what I recommend: Restrict ACS to patients for whom you have objective documentation of a high risk of spontaneous or indicated delivery before 34 weeks' gestation, such as a shortened cervix and/or positive vaginal fetal fibronectin with symptoms, or documented severe intrauterine growth restriction with abnormal Doppler flow studies, or definitive evidence of preeclampsia. Give ACS for preterm PROM only before 32 weeks in patients with no evidence of chorioamnionitis. In my opinion, there is insufficient evidence to recommend ACS for preterm PROM at 32 to 34 weeks unless amniocentesis has documented both fetal pulmonary immaturity and absence of intra-amniotic infection. Use betamethasone rather than dexamethasone, as the former is more effective and safer.17 If betamethasone isn't available, however, dexamethasone is acceptable. The earliest point at which, in consultation with your neonatologist, you would offer aggressive obstetric and neonatal interventions such as cesarean delivery and neonatal intubation is the soonest you should consider ACS. In my practice, that's 23 to 24 weeks, but ACS before 24 weeks may improve survival of severely damaged infants, and patients should be advised of that possibility. Use only one course of ACS in patients at risk for PTD after 28 weeks, pending results of future RCTs. Give a second dose of ACS—12 mg IM × 1, based on Crowther's data—to patients at 23 to 28 weeks' gestation who received the first course more than 7 days before and have documentation of an increased likelihood of PTD, such as further shortening of the cervix, newly positive fetal fibronectin with increased contractions, or deteriorating fetal or maternal condition. Do not, however, expose a fetus to more than two courses, outside of an investigative protocol. And counsel parents that while a repeat course of ACS likely will improve a fetus's short-term respiratory outcome, the long-term impact is unknown, and document the conversation in your records. REFERENCES 1. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol. 1969;45:515-523. 2. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50:515-525. 3. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev. 2000;(2):CD000065. 4. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consens Statement. 1994;12(2):1-24. 5. Trends and variations in use of antenatal corticosteroids to prevent neonatal respiratory distress syndrome: recommendations for national and international comparative audit. Scottish Neonatal Consultants' Collaborative Study Group, International Neonatal Network. Br J Obstet Gynaecol. 1996;103:534-540. 6. Chien LY, Ohlsson A, Seshia MM, et al. Canadian Neonatal Network. Variations in antenatal corticosteroid therapy: a persistent problem despite 30 years of evidence. Obstet Gynecol. 2002;99:401-408. 7. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 2000; 83:F177–F181. 8. French NP, Hagan R, Evans SF, et al. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol. 1999;180:114-121. 9. National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: repeat courses - National Institutes of Health Consensus Development Conference Statement, August 17-18, 2000. Obstet Gynecol. 2001;98:144-150. 10. Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial. JAMA. 2001;286:1581-1587. 11. Lee MJ, Davies J, Guinn D, et al. Single versus weekly courses of antenatal corticosteroids in preterm premature rupture of membranes. Obstet Gynecol. 2004;103:274-281. 12. Wapner RJ, Sorokin Y, Thom EA, et al. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol. 2006;195:633-642. 13. Crowther CA, Haslam RR, Hiller JE, et al; Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet. 2006;367:1913-1919. 14. French NP, Hagan R, Evans SF, et al. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol. 2004;190:588-595. 15. Dalziel SR, Walker NK, Parag V, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet. 2005;365:1856-1862. 16. Thorp JA, Jones PG, Knox E, et al. Does antenatal corticosteroid therapy affect birth weight and head circumference? Obstet Gynecol. 2002;99:101-108. 17. Lee BH, Stoll BJ, McDonald SA, et al.; National Institute of Child Health and Human Development Neonatal Research Network. Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics. 2006;117:1503-1510.
At Sun, 18 Feb 2007, Garry E. Siegel, M.D. wrote:
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-- “ The greatest obstacle to knowledge is not ignorance, it is the illusion of knowledge.” Daniel J. Boorstin - Historian
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