Extreme caution is needed before scale-up of antenatal corticosteroids to reduce preterm deaths in low-income settings
Authors: Kishwar Azad, Anthony Costello
Journal: The Lancet Global Health (2014)

The great American epidemiologist Bill Silverman taught us that the road to hell is paved with good intentions. From 1942, during a 12-year period, more than 10 000 infants were blinded through retinopathy of prematurity because paediatricians recommended a minor increase in the concentration of supplemental oxygen for preterm infants in incubators.1Silverman WA Retrolental fibroplasia: a modern parable. Grune & Stratton, New York1980Google Scholar Later, "untold thousands of premature infants succumbed in the first few days of life because incubator temperatures were set slightly too low (to avoid overheating)".2Silverman WA Medicine's 'therapeutic imperative' – haunted by the potential for tragedy.Paediatr Perinat Epidemiol. 2004; 18: 318-319Crossref PubMed Scopus (6) Google Scholar Indeed, Silverman's trial of adrenocorticotrophic hormone to treat retinopathy of prematurity showed no benefit and an increased death rate in the intervention group. He warned that we need trial evidence for any new preterm intervention. No shortcuts can be used—care of the preterm infant is a delicate and integrated process. Recently, antenatal corticosteroid treatment has been widely promoted to reduce preterm deaths in developing countries. On the face of it, the argument seems to be persuasive. Worldwide, 15 million infants are born prematurely every year, and south Asia accounts for two-thirds and Africa for three-quarters of deaths in these infants.3Lawn JE Davidge R Paul VK et al.Born too soon: care for the preterm baby.Reprod Health. 2013; 10: S5Crossref PubMed Scopus (149) Google Scholar The 2013 State of the World's Mothers report says: "Prenatal corticosteroids cost as little as 51 cents per treatment… are ready for rapid scale-up now…using skilled birth attendants…and could save 340 000 newborn lives each year".4Save the ChildrenSurviving the first day. State of the world's mothers. Save the Children, 2013Google Scholar This estimate does not come from trials but rather from a Lives Saved Analysis tool.4Save the ChildrenSurviving the first day. State of the world's mothers. Save the Children, 2013Google Scholar The evidence is far more nuanced. A systematic review of 21 studies in high-income and middle-income country hospitals, which included a total of 3885 women and 4269 infants, showed that one course of corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth reduced neonatal deaths by 31% (relative risk [RR] 0·69, 95% CI 0·58–0·81; in 18 studies of 3956 infants) and respiratory distress syndrome by 34% (0·66, 95% CI 0·59–0·73; in 21 studies of 4038 infants).5Roberts D Dalziel SR Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2006; 3 (CD004454)Google Scholar Nonetheless, the statement made by the Healthy Newborn Network that "administering antenatal steroids to a mom in preterm labour, helps her baby speed up lung development, reducing the risk of newborn death by more than 50% in low-resource facilities"—is speculative. The clamour to roll out a so-called magic bullet treatment must be resisted until three crucial questions have been answered. The first of these questions is whether antenatal corticosteroids actually work for mothers and infants at 33 weeks' gestation or less in poor populations? All studies in the systematic review were from hospitals in which infants had access to "level 2" special care: 24-h availability of skilled nursing; thermal stability; monitoring of blood gases, glucose, electrolytes, infection indicators, and bilirubin; apnoea alarms; oxygen and ventilatory support; and antibiotics and other essential drugs for infection and shock. Similar reductions in case-fatality rate are highly unlikely in settings where level 2 care is not available. Coverage of good-quality level 2 care in low-income settings is tiny—few facilities exist outside capital cities. One study of 1000 low-birthweight infants in Dhaka, Bangladesh, showed that even in a teaching hospital that provided level 2 care, three-quarters of neonates born at less than 33 weeks' gestation died during the neonatal period.6Yasmin S Paul E Osrin D Costello A Neonatal mortality of low-birth-weight infants in Bangladesh.Bull World Health Organ. 2001; 79: 608-614PubMed Google Scholar The causes of death were manifold and not just attributable to respiratory distress. Indeed, respiratory distress syndrome might be less prevalent in poor countries than in wealthy nations because intrauterine growth retardation causes fetal cortisol concentrations to rise, which might accelerate the production of lung surfactant. The second crucial question asks whether safety issues exist in poor settings. If steroids are given to millions of women in preterm labour in poor populations, can we be sure that there will be no significantly increased risk of maternal sepsis, perinatal death, or childhood disability? The 2006 systematic review showed that, from eight trials and 1003 women with data for puerperal sepsis, 57 of 496 treated mothers had sepsis, compared with 44 of 507 controls (RR 1·35, 95% CI 0·93–1·95). More worrying is the evidence from trials that used dexamethasone (the low-cost treatment recommended for scale-up), which significantly increased both puerperal sepsis (RR 1·74, 95% CI 1·04–2·89; in four trials of 536 women) and fever that needed antibiotics (2·05, 1·14–3·69; in one trial of 118 women), in comparatively wealthy populations.7Antenatal corticosteroids for the reduction of deaths in preterm babies. Working paper for the United Nations Commission on Life Saving Commodities.http://www.everywomaneverychild.org/images/Final_AN_Steroids_report_for_UN-COMPLETE.pdfDate: March 2012Google Scholar These findings ring alarm bells for scale-up in populations in which the prevalence of malnutrition and the risk of sepsis are much higher and access to antibiotics is low. In infants born at a gestation of at least 36 weeks, an almost significant trend was recorded towards an increase in combined fetal and neonatal death (RR 3·25, 95% CI 0·99–10·66; in two studies of 498 infants). Another major concern is that a substantially increased risk of disability can occur in cases where preterm survival is accompanied by suboptimum care. Historically, outcomes for preterm infants born at weights of less than 1500 g in developed countries showed that mortality rates and the prevalence of major disability in survivors were very high until after 1960 when level 2 care improved on a wide scale. The third crucial question is whether there is any evidence of benefit for the great majority of preterm infants born at more than 33 weeks? A recent working paper for the UN Commission on Life-Saving Commodities for Women and Children promotes scale-up of steroids by suggesting "the effect is greatest between 31 weeks and 36 weeks gestation" although no evidence shows an effect beyond 33 weeks.7Antenatal corticosteroids for the reduction of deaths in preterm babies. Working paper for the United Nations Commission on Life Saving Commodities.http://www.everywomaneverychild.org/images/Final_AN_Steroids_report_for_UN-COMPLETE.pdfDate: March 2012Google Scholar Three-quarters of the 12·6 million preterm infants worldwide each year are born after 33 completed weeks of gestation. In this group, the systematic review of antenatal steroids5Roberts D Dalziel SR Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2006; 3 (CD004454)Google Scholar showed no reduction in fetal or newborn deaths. For deaths in newborn babies alone, there was no benefit for babies born at 34 weeks or more (RR 1·58, 95% CI 0·71–3·50; two studies, 808 infants) or for babies born at 36 weeks or more (2·62, 95% CI 0·77–8·96, three studies, 514 infants). Moreover, there was no reduction in respiratory distress at more than 34 weeks, as we might expect from the timing of maturation of surfactant production. For these reasons, the American Academy of Obstetrics and Gynecology and the British Royal College of Obstetrics and Gynaecology both recommend steroid treatment for mothers only up to 33 weeks' gestation. With no evidence of benefit after 33 weeks in any setting, questionable benefit at less than 33 weeks in poor populations, potential risks of sepsis in mothers, and unknown disability levels in babies in cases where level 2 care standards are not met, we urge extreme caution. Millions of mothers in poor populations could soon be given steroid injections each year which carry risks that could substantially exceed the benefits. We support the existing recommendation to restrict single-dose antenatal steroids to mothers who are at 33 weeks' gestation or less, in preterm labour, and with easy access to good quality, round-the-clock level 2 care. We need clear evidence for benefit in other settings. One multicountry trial at established research sites in Argentina, Guatemala, Kenya, India, Pakistan, and Zambia is underway.8Althabe F Belizán JM Mazzoni A et al.Antenatal corticosteroids trial in preterm births to increase neonatal survival in developing countries: study protocol.Reprod Health. 2012; 9: 22Crossref PubMed Scopus (32) Google Scholar Other trials in poor and inaccessible populations are needed before we can be certain of the risk– benefit ratio. No quick fix exists to ensure preterm survival without serious disability. The global priority remains greater coverage of round-the-clock provision of high-quality level 2 care. The scope for low-cost innovation in district facilities is tremendous—eg, kangaroo care, the use of nursing aides to support scarce nursing staff, simple technology for blood sugar and bilirubin estimation, electricity-free syringe pumps, and low-cost incubators for babies too ill to manage skin-to-skin care. However, technology and drugs alone are dangerous without the provision and retention of skilled and motivated staff—the biggest challenge of all. We declare that we have no competing interests. Antenatal corticosteroids to reduce preterm deaths in low-income settingsIn their Comment (April issue),1 Kishwar Azad and Anthony Costello raise questions that should be answered before antenatal corticosteroid treatment is scaled up to reduce preterm deaths in low-income countries. We share their concerns about the unknown overall effect of this treatment on mortality and potential safety issues in the mother. To answer these questions, we have initiated the Antenatal Corticosteroids Trial2 to assess whether or not a multifaceted intervention to increase the use of antenatal corticosteroids reduces neonatal mortality at 28 days of age, and maternal morbidity due to infections. Full-Text PDF Open AccessAntenatal corticosteroids to reduce preterm deaths in low-income settingsIn their Comment1 on the use of antenatal corticosteroids to reduce preterm infant deaths, Kishwar Azad and Anthony Costello advise "extreme caution" before scale-up in low-income settings. They emphasise maternal sepsis as a concern but cite only one trial in which dexamethasone resulted in a significant increase in fever that required antibiotic treatment compared with controls (relative risk [RR] 2·05, 95% CI 1·14–3·69; 118 women).1,2 We suggest that this finding alone does not reflect a balanced assessment of the paucity of evidence available. Full-Text PDF Open AccessAntenatal corticosteroids to reduce preterm deaths in low-income settingsThe Comment1 by Kishwar Azad and Anthony Costello opposing scale-up of antenatal corticosteroids misdirects the discussion of this topic towards speculation about differences in low-income settings. Our experience in Malawi provides a concrete example of the rapid scaling up of antenatal corticosteroid treatment with dexamethasone. Full-Text PDF Open AccessAntenatal corticosteroids to reduce preterm deaths in low-income settings–Authors' replyWe agree with many of the correspondents' points. First, we concur that antenatal corticosteroid treatment can reduce respiratory distress in infants born at less than 34 weeks' gestation. Second, we welcome the rapid scale-up of its use in hospitals in Malawi, as described by Stephen Kaliti, and look forward to the published assessment of its effect on mortality in preterm infants. Third, we agree that more research is needed to explore the best methods for scale-up in hospitals and to assess the risks and benefits to patients through community studies in low-income regions. Full-Text PDF Open AccessAntenatal corticosteroids to reduce preterm deaths in low-income settingsKishwar Azad and Anthony Costello1 suggest the use of extreme caution in scaling up of antenatal corticosteroid treatment in low-income settings. They raise three important questions with respect to the efficacy, safety, and the appropriate gestational age at which to give corticosteroids to patients in low-income countries. Full-Text PDF Open Access