- Email: [email protected]
Antenatal corticosteroids to prevent preterm birth – Authors' reply
Correspondence
We welcome publication of the MACS trial report.1 What concerns us is that, in line with many earlier trials of single-course and with all trials of multiple-course antenatal steroids for preterm birth, infants with chorioamnionitis were excluded. In very preterm infants the incidence of clinical chorioamnionitis is around 10–30%. Thus, exclusion of these infants leads to an important reduction in external validity. Moreover, a growing body of evidence suggests that an opportunity is being missed when withholding antenatal steroids from infants with chorioamnionitis. In infants with signs of intrauterine inflammation, including clinical and histological chorioamnionitis, antenatal steroid administration is associated with reductions in respiratory distress syndrome, patent ductus arteriosus, systemic inflammatory response syndrome, severe cerebral lesions, cerebral palsy, and neonatal mortality.2–4 In a prospective cohort (n=301), we saw similar reductions in respiratory distress syndrome, intraventricular haemorrhage, ductus ligation, and mortality after antenatal steroids in infants with chorioamnionitis (unpublished data). Additionally, a meta-analysis of single-course studies showed particular benefit in infants with preterm, prelabour rupture of membranes, without an adverse effect on maternal outcome.5 Thus, whereas a general concern exists around antenatal steroid administration when intrauterine infection is suspected, recent studies leave no grounds for this fear and even seem to support this practice. We are in need of randomised trials of antenatal steroids that either focus on infants with chorioamnionitis or provide specific subgroup analysis for this group. Only then will we be able to validate or decline the generally restricted use of antenatal steroids in the setting of suspected intrauterine inflammation. We declare that we have no conflict of interest.
894
*Jasper V Been, Boris W Kramer, Luc J I Zimmermann [email protected] Department of Paediatrics, School for Oncology and Developmental Biology, Maastricht University Medical Centre, 6202 AZ Maastricht, Netherlands 1
2
3
4
5
Murphy KE, Hannah ME, Willan AR, et al, for the MACS Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008; 372: 2143–51. Been JV, Zimmermann LJ. Histologic chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 2009; published online Jan 8. DOI:10.1136/ adc.2008.150458. Kent A, Lomas F, Hurrion E, Dahlstrom JE. Antenatal steroids may reduce adverse neurological outcome following chorioamnionitis: neurodevelopmental outcome and chorioamnionitis in premature infants. J Paediatr Child Health 2005; 41: 186–90. Locatelli A, Ghidini A, Assi F, Andreani M, Malguzzi S, Paterlini G. Which factors affect the occurrence of severe cerebral lesions in preterm neonates who are born with intrauterine infection? Am J Obstet Gynecol 2008; 199: e1–5. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; 3: CD004454.
Authors’ reply Per Ashorn notes a 0·4-week difference in gestational age at birth between the placebo and the antenatal corticosteroid groups and questions whether this could be responsible for the differences found in birthweight and head circumference. The difference in gestational age at birth could possibly account for some of the differences in birthweight and head circumference, but not all of it, since more infants in the antenatal corticosteroid group than in the placebo group were small for gestational age (less than 10th centile) at birth (17% vs 14%, respectively). Gestational age at birth occurred after randomisation. Therefore any differences between the groups could be attributed to the intervention as a “post randomisation effect” and not necessarily by chance. Before randomisation, there was only a 9-g difference in estimated fetal weight between the antenatal corticosteroid and placebo groups on ultrasound assessment up to 2 weeks before randomisation. Thus we agree that some of the differences in birthweight
and head circumference could be explained by a difference in gestational age at birth. We plan to undertake secondary analyses to explore this possibility and to determine which other factors (eg, number of courses), contribute to the differences between the two groups in infants’ weight, head circumference, and length at birth. Jasper Been and colleagues wonder why we excluded women with chorioamnionitis from participation. Chorioamnionitis, even in the very preterm population, is an obstetric indication for expeditious delivery. Therefore, if randomised, the woman and her fetus would not have had an opportunity to experience the effects (benefits or harm) of the intervention. We declare that we have no conflict of interest.
*K E Murphy, M E Hannah, A R Willan, A Ohlsson, E Asztalos [email protected] Mount Sinai Hospital, Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Room 3726, Ontario Power Generation Building, 700 University Avenue, Toronto, ON M5R 1X5, Canada (KEM); Department of Obstetrics and Gynaecology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada (MEH); Programme in Child Health Evaluative Sciences, SickKids Research Institute, Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada (ARW); Department of Paediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada (AO); and Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada (EA)
Trade and health: dealing in death Thanks for your Comment on the global scale and gravity of the health consequences from unjust trade “rigged against the poorest countries” (Jan 24, p 273).1 The international trade described in The Lancet is largely done by corporations with identified board members, annual general meetings, and financial reports. The massive untaxed, unrecorded, and undercover trade in illicit drugs bleeds that global economy, widens local social inequalities, and directly undermines individual health. www.thelancet.com Vol 373 March 14, 2009
We welcome publication of the MACS trial report.1 What concerns us is that, in line with many earlier trials of single-course and with all trials of multiple-course antenatal steroids for preterm birth, infants with chorioamnionitis were excluded. In very preterm infants the incidence of clinical chorioamnionitis is around 10–30%. Thus, exclusion of these infants leads to an important reduction in external validity. Moreover, a growing body of evidence suggests that an opportunity is being missed when withholding antenatal steroids from infants with chorioamnionitis. In infants with signs of intrauterine inflammation, including clinical and histological chorioamnionitis, antenatal steroid administration is associated with reductions in respiratory distress syndrome, patent ductus arteriosus, systemic inflammatory response syndrome, severe cerebral lesions, cerebral palsy, and neonatal mortality.2–4 In a prospective cohort (n=301), we saw similar reductions in respiratory distress syndrome, intraventricular haemorrhage, ductus ligation, and mortality after antenatal steroids in infants with chorioamnionitis (unpublished data). Additionally, a meta-analysis of single-course studies showed particular benefit in infants with preterm, prelabour rupture of membranes, without an adverse effect on maternal outcome.5 Thus, whereas a general concern exists around antenatal steroid administration when intrauterine infection is suspected, recent studies leave no grounds for this fear and even seem to support this practice. We are in need of randomised trials of antenatal steroids that either focus on infants with chorioamnionitis or provide specific subgroup analysis for this group. Only then will we be able to validate or decline the generally restricted use of antenatal steroids in the setting of suspected intrauterine inflammation. We declare that we have no conflict of interest.
894
*Jasper V Been, Boris W Kramer, Luc J I Zimmermann [email protected] Department of Paediatrics, School for Oncology and Developmental Biology, Maastricht University Medical Centre, 6202 AZ Maastricht, Netherlands 1
2
3
4
5
Murphy KE, Hannah ME, Willan AR, et al, for the MACS Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008; 372: 2143–51. Been JV, Zimmermann LJ. Histologic chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 2009; published online Jan 8. DOI:10.1136/ adc.2008.150458. Kent A, Lomas F, Hurrion E, Dahlstrom JE. Antenatal steroids may reduce adverse neurological outcome following chorioamnionitis: neurodevelopmental outcome and chorioamnionitis in premature infants. J Paediatr Child Health 2005; 41: 186–90. Locatelli A, Ghidini A, Assi F, Andreani M, Malguzzi S, Paterlini G. Which factors affect the occurrence of severe cerebral lesions in preterm neonates who are born with intrauterine infection? Am J Obstet Gynecol 2008; 199: e1–5. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; 3: CD004454.
Authors’ reply Per Ashorn notes a 0·4-week difference in gestational age at birth between the placebo and the antenatal corticosteroid groups and questions whether this could be responsible for the differences found in birthweight and head circumference. The difference in gestational age at birth could possibly account for some of the differences in birthweight and head circumference, but not all of it, since more infants in the antenatal corticosteroid group than in the placebo group were small for gestational age (less than 10th centile) at birth (17% vs 14%, respectively). Gestational age at birth occurred after randomisation. Therefore any differences between the groups could be attributed to the intervention as a “post randomisation effect” and not necessarily by chance. Before randomisation, there was only a 9-g difference in estimated fetal weight between the antenatal corticosteroid and placebo groups on ultrasound assessment up to 2 weeks before randomisation. Thus we agree that some of the differences in birthweight
and head circumference could be explained by a difference in gestational age at birth. We plan to undertake secondary analyses to explore this possibility and to determine which other factors (eg, number of courses), contribute to the differences between the two groups in infants’ weight, head circumference, and length at birth. Jasper Been and colleagues wonder why we excluded women with chorioamnionitis from participation. Chorioamnionitis, even in the very preterm population, is an obstetric indication for expeditious delivery. Therefore, if randomised, the woman and her fetus would not have had an opportunity to experience the effects (benefits or harm) of the intervention. We declare that we have no conflict of interest.
*K E Murphy, M E Hannah, A R Willan, A Ohlsson, E Asztalos [email protected] Mount Sinai Hospital, Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Room 3726, Ontario Power Generation Building, 700 University Avenue, Toronto, ON M5R 1X5, Canada (KEM); Department of Obstetrics and Gynaecology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada (MEH); Programme in Child Health Evaluative Sciences, SickKids Research Institute, Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada (ARW); Department of Paediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada (AO); and Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada (EA)
Trade and health: dealing in death Thanks for your Comment on the global scale and gravity of the health consequences from unjust trade “rigged against the poorest countries” (Jan 24, p 273).1 The international trade described in The Lancet is largely done by corporations with identified board members, annual general meetings, and financial reports. The massive untaxed, unrecorded, and undercover trade in illicit drugs bleeds that global economy, widens local social inequalities, and directly undermines individual health. www.thelancet.com Vol 373 March 14, 2009