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News review 5. Dr Arun Sasi and Dr Ashok Deorari share their views on Repeat course of antenatal corticosteroids in preterm labor
Dr Arun Sasi & Prof Ashok Deorari
Division of Neonatology, Department of Pediatrics,
All India Institute of Medical Sciences,
New Delhi -110029
The use of antenatal corticosteroids for preterm labor was a revolutionary discovery, in perinatal medicine made way back in 1972, by Professor Graham Liggins and colleagues. There is overwhelming evidence for the use of single course of antenatal corticosteroids which is shown to enhance fetal maturation with reduction in neonatal mortality, respiratory distress syndrome (RDS) and intraventricular hemorrhage (IVH).
After one course (total of 24 mg of Betamethasone or Dexamethasone, given over 24 or 48 hours respectively) of antenatal steroid, the maximum benefits are seen if the fetus is delivered 24 hours after and within 7 days of the last dose. Because the beneficial effects wanes off after 7 days, it is conjectured, there might be benefit from repeated courses of antenatal steroids. However the use of repeated course of antenatal corticosteroids, though a prevalent clinical practice almost across the world, lacks robust evidence. The US National Institute of Health (NIH) consensus conference in 2000 endorsed their previous recommendations of use of single course of antenatal corticosteroids, made in 1994. However for repeat courses, they recommended that 'until data establish favorable risk- benefit ratio, repeat courses of antenatal corticosteroids, including rescue therapy, should be reserved for patients enrolled in clinical trials. The 2004, Royal College of Obstetricians and Gynecologists (RCOG) guidelines for use of antenatal corticosteroids are also similar to the NIH recommendations. Here we shall review the current evidence for use of multiple courses of antenatal corticosteroids. In 2001, Guinn et ali in a multi-centric randomized controlled trial (RCT) enrolled 500 women in preterm labor, to receive weekly course (2 doses of Betamethasone 12 mg, 24 hour apart) till weeks or delivery which ever was earlier. There was no difference in the composite outcome of neonatal morbidity score (presence of severe respiratory distress syndrome (RDS), bronchopulmonary dysplasia( BPD) , severe intra-ventricular hemorrhage, peri-ventricular leuckomalacia( PVL), proven sepsis, or death). In those with gestation less than 28 weeks there was significant reduction in RDS. The birth weight and head circumference though lower in the treated group, were not significantly different.
In 2006 Wapner et alii,iii as a part of the National Institute of child health and development (NICHD) Maternal Fetal Medicine units network trial, again a multi-centric RCT, enrolled 495 women between 23-31 weeks gestation with preterm labor to receive weekly repeat course of Betamethasone or placebo until delivery or 336/7 gestation which ever was earlier. There was no difference in the primary outcome- a composite of RDS, grade III or IV IVH, BPD or PVL between the groups. In babies with gestation less than 32 weeks, short term benefits like reduction in need for surfactant, mechanical ventilation, continuous positive pressure ventilation as well as reduced incidence of pneumothorax was seen. However there was trend towards reduced growth with lower birth weight in the repeated course group. There were also more newborns in the treated group with birth weight less than 10th and 5th centiles as compared to the placebo group. This study was terminated by the Data Safety Monitoring Committee after an interim analysis showing a reduction in growth without any benefit in terms of neonatal outcomes. In the long term follow up of these babies at. In the long term follow up of these babies at 24-36 months, there was no difference in growth parameter but a trend towards increased cerebral palsy was observed.
The Australian Collaborative Trial of Repeat Dose of Steroids (ACTORDS) conducted as multi-centric RCT, in Australia and New Zealand by Crowtheriv,v and colleagues enrolled 982 pregnant women less than 32 weeks to receive either single dose of intramuscular Betamethasone or saline placebo weekly till 32 weeks of gestation or delivery which ever was earlier. This study showed some short term benefits in the repeat corticosteroid group with significant reduction in RDS (33% vs. 41%, RR=0. 82[95% CI 0. 71- 0. 91]). There was also shorter duration of mechanical ventilation, lesser need for oxygen therapy and less severe lung disease. The mean weight, length and head circumference were not different. However the weight and head circumference Z scores were lower in the repeat steroid dose group. In the long term follow up of these infants at 18-22 months corrected age there was no difference in growth, major disability or lung disease between the two groups. There was increased occurrence of attention problems in repeat steroid group.
In 2007, Peltoniemi et all in a randomized controlled trial from Finland examined the role repeat single booster dose of Betamethasone before delivery, in 249 pregnant women. The trial was terminated prematurely as there was an increase in RDS and need for surfactant therapy in the treatment group.
In 2008, the Multiple courses of antenatal corticosteroids for preterm birth (MACS) trial was published by Murphy et alvi. Till date this is the largest trial, on use of repeat course of antenatal corticosteroids for women in preterm labor. This was a double blind placebo controlled multicenteric RCT, enrolling 1885 pregnant women between 25-32 weeks gestation, from 80 centers in 20 countries. The treatment group received repeat course (2 doses) of 12 mg Betamethasone (6mg Betamethasone sodium phosphate and 6 mg Betamethasone sodium acetate) every 14 days till delivery or 336/7 weeks gestation which ever was earlier. The was no difference between the groups in terms of a composite of mortality, severe RDS, severe IVH, PVL, BPD or necrotizing entero-colitis (NEC) . The need for ventilation, surfactant, O2 post resuscitation as well as duration of hospital stay was not different between the two groups. Infants in the multiple corticosteroids were significantly smaller at birth with weight less by 114 gm, head circumference less by 0.6cm and length less by 0.9 cm.
In the subgroup of infants < 32 weeks as well as those born within 7 days of the repeat course also did not show any benefit. Hence the authors concluded "overall, multiple courses of antenatal corticosteroids, given every 14 days, are associated with decreased growth in utero and no neonatal benefi ts compared with one course of antenatal corticosteroids. Therefore, in women who remain at increased risk of preterm birth after receiving an initial course of antenatal corticosteroids, multiple courses every 14 days are not recommended"
In a recent randomized controlled trial from a tertiary care centre from India, Mazumder et alvii compared the beneficial effects and adverse effects of single vs. multiple courses of antenatal Betamethasone in pregnant women from 25-32 weeks gestation with risk for preterm delivery. The primary outcome i.e. severe RDS was similar between the two groups as was the incidence of other neonatal morbidity like IVH, NEC, ROP, PDA and sepsis. The anthropometry at birth was not different but at 6 months the weight and length were significantly lower in the multiple course steroid group. Head circumference and neuro-developmental outcome at birth was not different at 6 months Finally the Cochrane review in 2007 by Crowther et al which included 5 trials involving around 2000 pregnant women, showed 18% reduction in RDS, 40% reduction in severe lung disease, and 21% reduction in mortality. Growth and other outcomes were not different though babies in repeat course of steroids were more likely to be small for gestation.
To conclude repeat doses of antenatal corticosteroids in preterm labor may reduce the incidence and severity of respiratory distress syndrome. However, there is reduction of growth at birth as well as trend towards adverse long term neuro-developmental outcome. In the light of current level of evidence, the practice of repeat doses of antenatal corticosteroids in preterm labor cannot be recommended.
- Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. (Am J Obstet Gynecol. 2006 Sep; 195(3):633-42)
Wapner RJ, Sorokin Y, Thom EA, Johnson F, Dudley DJ, Spong CY, Peaceman AM, Leveno KJ, Harper M, Caritis SN, Miodovnik M, Mercer B, Thorp JM, Moawad A, O'Sullivan MJ, Ramin S, Carpenter MW, Rouse DJ, Sibai B, Gabbe SG; National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network. Objective: The purpose of this study was to determine if weekly corticosteroids improve neonatal outcome without undue harm.
Study Design: Women 23 to 32 weeks receiving 1 course of corticosteroids 7 to 10 days prior were randomized to weekly betamethasone or placebo.
Results: The study was terminated by the independent data and safety monitoring committee with 495 of the anticipated 2400 patients enrolled. There was no significant reduction in the composite primary morbidity outcome (8.0% vs 9.1%, P = .67). Repeated courses significantly reduced neonatal surfactant administration (P = .02), mechanical ventilation (P = .004), CPAP (P = .05), pneumothoraces (P = .03). There was no significant difference in mean birth weight or head circumference. The repeat group had a reduction in multiples of the birth weight median by gestational age (0.88 vs 0.91) (P = .01) and more neonates weighing less than the 10th percentile (23.7 vs 15.3%, P = .02). Significant weight reductions occurred for the group receiving > or = 4 courses.
Conclusion: Repeat antenatal corticosteroids significantly reduce specific neonatal morbidities but do not improve composite neonatal outcome. This is accompanied by reduction in birth weight and increase in small for gestational age infants. - Long-term outcomes after repeat doses of antenatal corticosteroids.
(N Engl J Med. 2007 Sep 20; 357(12):1190-8)
Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY, Peaceman AM, Leveno KJ, Malone F, Caritis SN, Mercer B, Harper M, Rouse DJ, Thorp JM, Ramin S, Carpenter MW, Gabbe SG; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
Background: Previous trials have shown that repeat courses of antenatal corticosteroids improve some neonatal outcomes in preterm infants but reduce birth weight and increase the risk of intrauterine growth restriction. We report long-term follow-up results of children enrolled in a randomized trial comparing single and repeat courses of antenatal corticosteroids.
Methods: Women at 23 through 31 weeks of gestation who remained pregnant 7 days after an initial course of corticosteroids were randomly assigned to weekly courses of betamethasone, consisting of 12 mg given intramuscularly and repeated once at 24 hours, or an identical-appearing placebo. We studied the children who were born after these treatments when they were between 2 and 3 years of corrected age. Pre-specified outcomes included scores on the Bayley Scales of Infant Development, anthropometric measurements, and the presence of cerebral palsy.
Results: A total of 556 infants were available for follow-up; 486 children (87.4%) underwent physical examination and 465 (83.6%) underwent Bayley testing at a mean (+/-SD) corrected age of 29.3+/-4.6 months. There were no significant differences in Bayley results or anthropometric measurements. Six children (2.9% of pregnancies) in the repeat-corticosteroid group had cerebral palsy as compared with one child (0.5% of pregnancies) in the placebo group (relative risk, 5.7; 95% confidence interval, 0.7 to 46.7; P=0.12). Conclusions: Children who had been exposed to repeat as compared with single courses of antenatal corticosteroids did not differ significantly in physical or neurocognitive measures. Although the difference was not statistically significant, the higher rate of cerebral palsy among children who had been exposed to repeat doses of corticosteroids is of concern and warrants further study.
- Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids:a randomized controlled trial. Lancet. 2006 Jun 10;367(9526):1913-9)
Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS; Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group.
Background: The efficacy and safety of repeat doses of prenatal corticosteroids remains uncertain. Our aim was to establish whether repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm. Methods: In this hospital-based study, 982 women who remained at risk of preterm birth at less than 32 weeks' gestation, 7 or more days after receiving a first course of prenatal corticosteroids, were randomly assigned to receive a repeat intramuscular dose of either 11.4 mg betamethasone (as Celestone Chronodose), or saline placebo. This was repeated every week the woman remained undelivered, at less than 32 weeks' gestation, and at risk of preterm birth. Primary outcomes were occurrence and severity of neonatal respiratory distress syndrome, use and duration of oxygen and mechanical ventilation, and weight, length, and head circumference at birth and hospital discharge. Statistical analyses were on an intention to treat basis.
Results: Fewer babies exposed to repeat corticosteroids had respiratory distress syndrome (33%vs 41%; relative risk 0.82, 95% CI 0.71-0.95, p=0.01) and fewer had severe lung disease (12%vs 20%; relative risk 0.60, 95% CI 0.46-0.79, p=0.0003) than those in the placebo group. In keeping with these benefits, babies exposed to repeat corticosteroids needed less oxygen therapy (p=0.03), and shorter duration of mechanical ventilation (p=0.01). Mean weight, length, and head circumference at birth and hospital discharge did not differ between treatment groups. Z-scores for weight (p=0.04) and head circumference (p=0.03) at birth were lower in the babies who received repeat corticosteroids although at the time of hospital discharge Z-scores did not differ between treatment groups (p=0.29 for weight, p=0.48 for head circumference). Conclusion: Exposure to repeat doses of antenatal corticosteroids reduces neonatal morbidity. Pending long-term outcome results, the short-term benefits for the babies in our study support the use of repeat doses of corticosteroids in women who remain at risk of very preterm birth 7 or more days after an initial course.
- Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.
N Engl J Med. 2007 Sep 20; 357(12):1179-89.
Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS; ACTORDS Study Group.
Background: We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment.
Methods: Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neuro-sensory disability and body size of the children at 2 years of corrected age.
Results: Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04).
Conclusions: Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neuro-sensory disability or body size at 2 years - Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.(Pediatrics. 2007 Feb;119(2):290-8)
Peltoniemi OM, Kari MA, Tammela O, Lehtonen L, Marttila R, Halmesmäki E, Jouppila P, Hallman M; Repeat Antenatal Betamethasone Study Group.
Background: A single dose of prenatal betamethasone treatment decreases neonatal morbidity rates when administered within 7 days before preterm delivery. A single repeat dose or booster dose of betamethasone before delivery has been proposed to be effective, but its efficacy has not been subjected to a randomized, blinded trial.
Methods: Women with imminent delivery before 34.0 gestational weeks were eligible if they remained without delivery for >7 days after a single course of betamethasone. After stratification, a single repeat dose of betamethasone (12 mg) or placebo was administered. The primary outcome was survival without respiratory distress syndrome or severe intra-ventricular hemorrhage (grade 3 or 4).
Results: A total of 249 mothers had been enrolled by the time the study was discontinued. All of the 159 infants in the betamethasone group and 167 in the placebo group were born before 36 weeks of gestation. The intact survival rate was unaffected and was lower than anticipated, because the gestational age-adjusted incidence of respiratory distress syndrome was higher than the population incidence. The requirement for surfactant therapy in respiratory distress syndrome was increased in the betamethasone group. According to posthoc analysis of the data for 206 infants who were delivered within 1 to 24 hours, the betamethasone booster tended to increase the risk of respiratory distress syndrome and to decrease intact survival rates.
Conclusions: According to this study, a single booster dose of betamethasone just before preterm birth may perturb respiratory adaptation. These results caution against uncontrolled use of a repeat dose of glucocorticoids in high-risk pregnancies. - Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomized controlled trial. ( Lancet. 2008 Dec 20;372(9656):2143-51)
Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly EN, Matthews SG, Saigal S, Asztalos E, Ross S, Delisle MF, Amankwah K, Guselle P, Gafni A, Lee SK, Armson BA; MACS Collaborative Group.
Background: One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death. Weekly doses given to women who remain undelivered after a single course may have benefits (less respiratory morbidity) or cause harm (reduced growth in- utero). We aimed to find out whether multiple courses of antenatal corticosteroids would reduce neonatal morbidity and mortality withouReferencest adversely affecting fetal growth.
Methods: 1858 women at 25-32 weeks' gestation who remained undelivered 14-21 days after an initial course of antenatal corticosteroids and continued to be at high risk of preterm birth were randomly assigned to multiple courses of antenatal corticosteroids (n=937) or placebo (n=921), every 14 days until week 33 or delivery, whichever came first. The primary outcome was a composite of perinatal or neonatReferencesal mortality, severe respiratory distress syndrome, intra-ventricular haemorrhage (grade III or IV), peri-ventricular leucomalacia, bronchopulmonary dysplasia, or necrotising enterocolitis. Analysis was by intention to treat. All patients and caregivers were unaware of the treatment given.
Results: Infants exposed to multiple courses of antenatal corticosteroids had similar morbidity and mortality to those exposed to placebo (150 [12.9%] vs 143 [12.5%]). Those receiving multiple doses of corticosteroids also weighed less at birth than those exposed to placebo (2216 g vs 2330 g, p=0.0026), were shorter (44.5 cm vs 45.4 cm, p<0.001), and had a smaller head circumference (31.1 cm vs 31.7 cm, p<0.001).
Conclusion: Multiple courses of antenatal corticosteroids, every 14 days, do not improve preterm-birth outcomes, and are associated with a decreased weight, length, and head circumference at birth. Therefore, this treatment schedule is not recommended. - Single versus Multiple Courses of Antenatal Betamethasone and Neonatal Outcome:A Randomized Controlled Trial.
Mazumder P, Dutta S, Kaur J, Anil Narang∙ Ind Ped 2008; 45:661-668.
This study compared the beneficial and adverse neonatal effects of a single versus repeated courses of antenatal betamethasone.
Setting: Tertiary care hospital Design: Open labeled randomized controlled trial.
Participants: Pregnant women (26-33 weeks) at risk of preterm delivery, who received one course of antenatal betamethasone and remained undelivered for 7 days. Those with uncertain gestation, major malformations and frank chorio-amnionitis were excluded.
Interventions: Subjects were randomized to receive weekly antenatal betamethasone until 34 weeks or no further betamethasone.
Outcome measures: Primary: incidence of severe respiratory distress syndrome (RDS). Secondary: incidence of non-severe RDS and other neonatal morbidity; birth weight, length and occipito-frontal circumference (OFC); and development and growth at 6 mo corrected age.
Results: 38 subjects were allocated to each group. Severe RDS was similar in multiple and single course groups (7% vs. 3% respectively, P= 0.34), as was incidence of other morbidity. Composite outcome of "RDS and/or death within 28 d" tended to be less in multiple course group (P= 0.07). Birth anthropometry was similar in the 2 groups. At 6 mo corrected age (n=44), weight and length were significantly lower in multiple course group (p= 0.003 and P= 0.007, respectively), whereas OFC was not different (P= 0.1). There were no differences vis-a-vis neurodevelopmental outcomes.
Conclusions: A single course of antenatal betamethasone was as efficacious as multiple courses, with respect to prevention of neonatal morbidity. Multiple antenatal betamethasone courses have long-term adverse effects on infant weight and length growth, but not on OFC and neurodevelopment. - Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth
Crowther CA, Harding JE. Cochrane Database Syst Rev. 2007 Jul 18 ;( 3):CD003935. Background: It is not clear whether there is benefit in repeating the dose of prenatal corticosteroids for women who remain at risk of preterm birth after an initial course.
Objectives: To assess the effectiveness and safety of a repeat dose(s) of prenatal corticosteroids.
Selection Criteria: Randomized controlled trials of women who have already received a single course of corticosteroids seven or more days previously and are still considered to be at risk of preterm birth; outcomes compared for women randomized to receive a repeat dose(s) of prenatal corticosteroids, with women given no further prenatal corticosteroids.
Main results: Five trials, involving over 2000 women between 23 and 33 weeks' gestation, are included. Treatment with repeat dose(s) of corticosteroid was associated with a reduction in occurrence (relative risk (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.93, four trials, 2155 infants) and severity of any neonatal lung disease (RR 0.60, 95% CI 0.48 to 0.75, three trials, 2139 infants) and serious infant morbidity (RR 0.79, 95% CI 0.67 to 0.93, four trials, 2157 infants).Mean birth weight was not significantly different between treatment groups (weighted mean difference (WMD) -62.07 g, 95% CI -129.10 to 4.96, four trials, 2273 infants), although in one trial, treatment with repeat dose(s) of corticosteroid was associated with a reduction in birth weight Z score (WMD) -0.13, 95% CI -26 to 0.00, 1 trial, 1144 infants), and in two trials, with an increased risk of being small for gestational age at birth (RR 1.63, 95% CI 1.12 to 2.37, two trials, 602 infants).No statistically significant differences were seen for any of the other primary outcomes that included other measures of respiratory morbidity, fetal and neonatal mortality, peri-ventricular hemorrhage, peri-ventricular leukomalacia and maternal infectious morbidity. Treatment with repeat dose(s) of corticosteroid was associated with a significantly increased risk of caesarean section (RR 1.11, 95% CI 1.01 to 1.22, four trials, and 1523 women). Conclusions: Repeat dose(s) of prenatal corticosteroids reduce the occurrence and severity of neonatal lung disease and the risk of serious health problems in the first few weeks of life. These short-term benefits for babies support the use of repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth. However, these benefits are associated with a reduction in some measures of weight, and head circumference at birth, and there is still insufficient evidence on the longer-term benefits and risks. - 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. J Am Med Assoc 2001; 286:1581-7.
- 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; 195:633-42.
- Wapner RJ, Sorokin Y, Mele L, et al. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1190-8.
- Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomized controlled trial. Lancet 2006; 367:1913-9.
- Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357:1179-89.
- Murphy KE, Hannah ME, Willan AR, et al. Multiple c) 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. J Am Med Assoc 2001; 286:1581-7.
ourses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008; 372:2143-51. - Mazumder P, Dutta S, Kaur J, Narang A. Single versus multiple courses of antenatal betamethasone and neonatal outcome: A randomized controlled trial. Indian Pediatr 2008; 45: 661-667.
- Crowther CA, Harding JE Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2007 Jul 18 ;( 3):CD003935.
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