Trials Of Antenatal Corticosteroids Research Articles

The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- resource countries

BackgroundPreterm birth complications are the leading cause of newborn and under-5 mortality. Over 85% of all preterm births occur in the late preterm period, i.e. between 34 and < 37 weeks of gestation. Antenatal corticosteroids (ACS) prevent mortality and respiratory morbidity when administered to women at high risk of an early preterm birth, i.e. < 34 weeks’ gestation. However, the benefits and risks of ACS in the late preterm period are less clear; both guidelines and practices vary between settings. Emerging evidence suggests that the benefits of ACS may be achievable at lower doses than presently used. This trial aims to determine the efficacy and safety of two ACS regimens compared to placebo, when given to women with a high probability of late preterm birth, in hospitals in low-resource countries.MethodsWHO ACTION III trial is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens: dexamethasone phosphate 4 × 6 mg q12h or betamethasone phosphate 4 × 2 mg q 12 h. The trial is being conducted across seven sites in five countries—Bangladesh, India, Kenya, Nigeria, and Pakistan. Eligible women are those with a gestational age between 34 weeks 0 days and 36 weeks 5 days, who have a high probability of preterm birth between 12 h and 7 days (up to 36 weeks 6 days gestation). The primary outcome is a composite of stillbirth or neonatal death within 72 h of birth or use of newborn respiratory support within 72 h of birth or prior to discharge from hospital, whichever is earlier. Secondary outcomes include safety and health utilization measures for both women and newborns. The sample size is 13,500 women.DiscussionThis trial will evaluate the benefits and possible harms of ACS when used in women likely to have a late preterm birth. It will also evaluate a lower-dose ACS regimen based on literature from pharmacokinetic studies. The results of this trial will provide robust critical evidence on the safe and appropriate use of ACS in the late preterm period internationally.Trial registrationISRCTN11434567. Registered on 7 June 2021.

Randomised placebo-controlled trial of antenatal corticosteroids for planned birth in twins (STOPPIT-3): study protocol

IntroductionThe aim of the STOPPIT-3 study is to determine the clinical and cost effectiveness of antenatal corticosteroids (ACS) prior to planned birth of twins in a multicentre placebo-controlled trial with...

Betamethasone for Preterm Birth: Auckland Steroid Trial Full Results and New Insights 50 Years on

The objective of this study was to use modern analysis and reporting methods to present the full results of the first randomized trial of antenatal corticosteroids, performed 50years ago. In this single-center trial, women at risk of preterm birth at 24 to less than 37weeks of gestationwere randomized to receive 2 doses of betamethasone or placebo, 24hours apart. Women and their caregivers were blinded to treatment allocation. The primary outcome was respiratory distress syndrome. Secondary outcomes included measures of neonatal mortality and morbidity, mode of birth, and maternal infection. Between 1969 and 1974, 1115 women (1142 pregnancies) were randomized, 560 pregnancies (601 infants) to betamethasone and 582 (617 infants) to placebo. The risk of respiratory distress syndrome was significantly reduced in the betamethasone group compared with placebo (8.8% vs 14.4%, adjusted relative risk 0.62, 95% CI 0.45-0.86, P=.004). Subgroup analyses indicated greater efficacy in male than female infants but no effect of tocolytic therapy or doubling of betamethasone dose. Fetal or neonatal death, neonatal or maternal infection, neonatal hypoglycaemia, cesarean delivery, and lactation status at discharge were not different between the groups. Antenatal betamethasone administered to women at risk of preterm birth between 24 and less than 37weeks of gestation reduces the incidence of respiratory distress syndrome, with greater effect in male than in female infants. Doubling the dose of betamethasone does not provide additional benefit.

Improving the external validity of Antenatal Late Preterm Steroids trial findings.

The external validity of randomised trials can be compromised when trial participants differ from real-world populations. In the Antenatal Late Preterm Steroids (ALPS) trial of antenatal corticosteroids at late preterm ages, participants had systematically younger gestational ages than those outside the trial setting. As risk of respiratory morbidity (the primary trial outcome) is higher at younger gestations, absolute benefits of corticosteroids calculated in the trial population may overestimate real-world treatment benefits. To estimate the real-world absolute risk reduction and number-needed-to-treat (NNT) for antenatal corticosteroids at late preterm ages, accounting for gestational age differences between the ALPS and real-world populations. Individual participant data from the ALPS trial (which recruited 2831 women with imminent preterm birth at 34+0 to 36+5weeks') was appended to population-based data for 15,741 women admitted for delivery between 34+0 and 36+5weeks' from British Columbia, Canada, 2000-2013. We used logistic regression to calculate inverse odds of sampling weights for each trial participant and re-estimated treatment effects of corticosteroids on neonatal respiratory morbidity in ALPS participants, weighted to reflect the gestational age distribution of the population-based (real-world) sample. The real-world absolute risk reduction was estimated to be -2.2 (95% CI -4.6, 0.0) cases of respiratory morbidity per 100, compared with -2.8 (95% CI -5.3, -0.3) in original trial data. Corresponding NNTs were 46 in the real-world setting vs 35 in the trial. Our focus on absolute measures also highlighted that the benefits of antenatal corticosteroids may be meaningfully greater at 34weeks vs. 36weeks (e.g., risk reductions of -3.7 vs. -1.2 per 100 respectively). The absolute risk reductions and NNTs associated with antenatal corticosteroid administration at late preterm ages estimated in our study may be more appropriate for patient counselling as they better reflect the anticipated benefits of treatment when used in a real-world situation.

Antenatal Glucocorticoids in Low-Resource Settings—Who, When, and Where?

(N Engl J Med. 2020;383:2584–2585) Glucocorticoid therapy has been long known to improve neonatal outcomes in preterm birth. The data supporting the use of antenatal glucocorticoids largely comes from high-resource countries. The Antenatal Corticosteroids Trial (ACT) published in 2015 investigated the use of antenatal dexamethasone in settings with limited access to obstetricians and neonatal intensive care. ACT found antenatal dexamethasone did not lower mortality among neonates with a birth weight below the fifth percentile (a proxy for preterm birth), but instead increased overall neonatal mortality compared with placebo (27.4 vs. 23.9 deaths/1000 live births) and increased the incidence of suspected maternal infection (3% to 2%).

Factors Associated with Formula Feeding among Late Preterm Neonates.

Late preterm births (delivery at 34-36 weeks) account for nearly three quarters of the preterm births and among them there is a knowledge gap about an important aspect of infant care: breast versus formula feeding. The aim of this study was to assess factors associated with formula feeding in late preterm neonates. Secondary analysis of a multicenter randomized trial of antenatal corticosteroids for women at risk for late preterm birth. All women with a singleton pregnancy who delivered at 340/7 to 366/7 weeks were included. Women with no information on neonatal feeding or known fetal anomalies were excluded. The outcome evaluated was the type of neonatal feeding during hospital stay. Maternal and neonatal characteristics were compared among women who initiated breast versus formula feeding. Adjusted relative risks (aRRs) for formula feeding with 95% confidence intervals (CIs) were calculated. Of the 2,831 women in the parent trial, 2,329 (82%) women met inclusion criteria and among them, 696 (30%) were formula feeding. After multivariable regression, the following characteristics were associated with an increased risk of formula feeding: maternal age < 20 years (aRR: 1.47, 95% CI: 1.20-1.80) or ≥35 years (aRR: 1.19, 95% CI: 1.02-1.40), never married status (aRR: 1.39, 95% CI: 1.20-1.60), government-assisted insurance (aRR: 1.41, 95% CI: 1.16-1.70), chronic hypertension (aRR: 1.19, 95% CI: 1.01-1.40), smoking (aRR: 1.51, 95% CI: 1.31-1.74), cesarean delivery (aRR: 1.16, 95% CI: 1.03-1.32), and admission to neonatal intensive care unit (aRR: 1.31, 95% CI: 1.16-1.48). Hispanic ethnicity (aRR: 0.78, 95% CI: 0.64-0.94), education >12 years (aRR: 0.81, 95% CI 0.69-0.96), and nulliparity (aRR 0.71, 95% CI: 0.62-0.82) were associated with a reduced risk for formula feeding. In this geographically diverse cohort of high-risk deliveries, 3 out 10 late preterm newborns were formula fed. Smoking cessation was a modifiable risk factor that may diminish the rate of formula feeding among late preterm births. · Three of ten late preterm do not benefit from breastfeeding.. · Demographic characteristics are associated with type of feeding.. · Smoking cessation may improve the rate of breastfeeding..

Neonatal morbidity in late preterm small for gestational age neonates

Introduction To compare neonatal respiratory morbidity among small for gestational age (SGA; birth weight less than 10th percentile for gestational age) versus appropriate for gestational age (AGA; BW at 10–90th percentile) neonates born in the late preterm period. Methods A secondary analysis of a multicenter randomized trial of antenatal corticosteroids for women at risk for late preterm birth. Singleton, nonanomalous, AGA or SGA births that delivered at 34–36 weeks were included. Women were excluded if they delivered after 37 weeks or had a large for gestational age baby (LGA; weight over 90th for gestational age). The primary outcome was a composite of any of the following: respiratory support by 72 h (continuous positive airway pressure or high flow nasal cannula ≥2 h, oxygen with a fraction of inspired oxygen of ≥30% for ≥4 h, extra corporeal membrane oxygenation or mechanical ventilation) or neonatal death. The secondary outcomes included several neonatal and maternal morbidities. Multivariable Poisson regression models were used to examine the association between neonatal weight and outcomes (using adjusted relative risk [aRR] and 95% confidence intervals [CI]). Results Of the 2831 women in the parent trial, 2315 (82%) women met inclusion criteria; among them, 426 (18%) of the neonates were SGA. There was no significant difference in the risk of the primary outcome between SGA and AGA (13.1 versus 15.1%, aRR 0.85, 95% CI 0.66–1.10). SGA, however, was associated with an increased risk for neonatal intensive care unit admission (68 versus 45%, aRR 1.60, 95% CI 1.47–1.74), hypothermia (12.2 versus 8.8%, aRR 1.36, 95% CI 1.01–1.83), feeding problems (47.2 versus 36.9%, aRR 1.24, 95% CI 1.07–1.45) and a decreased risk of neonatal hyperbilirubinemia (7.5 versus 12.7%, aRR 0.59, 95% CI 0.41–0.84), when compared to AGA. Conclusion In this cohort of late preterm birth, there was no significant difference in the rate of composite respiratory morbidity between SGA and AGA newborns.

The World Health Organization ACTION-I (Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns) Trial: a multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries

BackgroundAntenatal corticosteroids (ACS) have long been regarded as a cornerstone intervention in mitigating the adverse effects of a preterm birth. However, the safety and efficacy of ACS in hospitals in low-resource countries has not been established in an efficacy trial despite their widespread use. Findings of a large cluster-randomized trial in six low- and middle-income countries showed that efforts to scale up ACS use in low-resource settings can lead to harm. There is equipoise regarding the benefits and harms of ACS use in hospitals in low-resource countries. This randomized controlled trial aims to determine whether ACS are safe and efficacious when given to women at risk of imminent birth in the early preterm period, in hospitals in low-resource countries.Methods/designThe trial design is a parallel, two-arm, double-blind, individually randomized, placebo-controlled trial of ACS (dexamethasone) for women at risk of imminent preterm birth. The trial will recruit 6018 women in participating hospitals across five low-resource countries (Bangladesh, India, Kenya, Nigeria and Pakistan). The primary objectives are to compare the efficacy of dexamethasone with placebo on survival of the baby and maternal infectious morbidity. The primary outcomes are: 1) neonatal death (to 28 completed days of life); 2) any baby death (any stillbirth postrandomization or neonatal death); and 3) a composite outcome to assess possible maternal bacterial infections. The trial will recruit eligible, consenting pregnant women from 26 weeks 0 days to 33 weeks 6 days gestation with confirmed live fetuses, in whom birth is planned or expected within 48 h. The intervention comprises a regimen of intramuscular dexamethasone sodium phosphate. The comparison is an identical placebo regimen (normal saline). A total of 6018 women will be recruited to detect a reduction of 15% or more in neonatal deaths in a two-sided 5% significance test with 90% power (including 10% loss to follow-up).DiscussionFindings of this trial will guide clinicians, programme managers and policymakers on the safety and efficacy of ACS in hospitals in low-resource countries. The trial findings will inform updating of the World Health Organization’s global recommendations on ACS use.Trial registrationACTRN12617000476336. Registered on 31 March 2017.

Cost-effectiveness of Antenatal Corticosteroid Therapy vs No Therapy in Women at Risk of Late Preterm Delivery

Administration of corticosteroids to women at high risk for delivery in the late preterm period (34-36 weeks' gestation) improves short-term neonatal outcomes. The cost implications of this intervention are not known. To compare the cost-effectiveness of treatment with antenatal corticosteroids with no treatment for women at risk for late preterm delivery. This secondary analysis of the Antenatal Late Preterm Steroids trial, a multicenter randomized clinical trial of antenatal corticosteroids vs placebo in women at risk for late preterm delivery conducted from October 30, 2010, to February 27, 2015. took a third-party payer perspective. Maternal costs were based on Medicaid rates and included those of betamethasone, as well as the outpatient visits or inpatient stay required to administer betamethasone. All direct medical costs for newborn care were included. For infants admitted to the neonatal intensive care unit, comprehensive daily costs were stratified by the acuity of respiratory illness. For infants admitted to the regular newborn nursery, nationally representative cost estimates from the literature were used. Effectiveness was measured as the proportion of infants without the primary outcome of the study: a composite of treatment in the first 72 hours of continuous positive airway pressure or high-flow nasal cannula for 2 hours or more, supplemental oxygen with a fraction of inspired oxygen of 30% or more for 4 hours or more, and extracorporeal membrane oxygenation or mechanical ventilation. This secondary analysis was initially started in June 2016 and revision of the analysis began in May 2017. Betamethasone treatment. Incremental cost-effectiveness ratio. Costs were determined for 1426 mother-infant pairs in the betamethasone group (mean [SD] maternal age, 28.6 [6.3] years; 827 [58.0%] white) and 1395 mother-infant pairs in the placebo group (mean [SD] maternal age, 27.9 [6.2] years; 794 [56.9%] white). Treatment with betamethasone was associated with a total mean (SD) woman-infant-pair cost of $4681 ($5798), which was significantly less than the mean (SD) amount of $5379 ($8422) for women and infants in the placebo group (difference, $698; 95% CI, $186-$1257; P = .02). The Antenatal Late Preterm Steroids trial determined that betamethasone use is effective: respiratory morbidity decreased by 2.9% (95% CI, -0.5% to -5.4%). Thus, the cost-effectiveness ratio was -$23 986 per case of respiratory morbidity averted. Inspection of the bootstrap replications confirmed that treatment was the dominant strategy in 5000 samples (98.8%). Sensitivity analyses showed that these results held under most assumptions. The findings suggest that antenatal betamethasone treatment is associated with a statistically significant decrease in health care costs and with improved outcomes; thus, this treatment may be an economically desirable strategy.

Trials of antenatal corticosteroids for preterm fetal lung maturity: a review of the potential for selective outcome reporting

ObjectiveTo measure the extent to which the evidence underpinning prenatal corticosteroids for preterm fetal lung maturity is at risk of bias due to selective outcome reporting. Study designFive biomedical databases (Medline, ClinicalTrials.gov, Embase, OVID and HMIC) were searched for trials published between February 2016 and September 2017.Randomised trials of prenatal steroids for women at risk of preterm birth were identified. For each, we recorded the registration status and timing, and whether the registered primary outcome had been reported. For unregistered trials, we estimated the potential for selective outcome reporting indirectly by tabulating all reported outcomes and by comparing the first outcome reported in the methods to the first in the results section. ResultsTwenty seven trials were identified. Only three (11%) trials had been registered. All three reported their pre-specified primary outcome. Among the unregistered trials, thirteen (54%) had different first reported outcomes in the methods and results sections, and among all trials many different outcomes were reported suggesting considerable potential for selective reporting. However, the single outcome of respiratory distress syndrome, albeit defined in different ways, was reported in all but two trials. This is reassuring evidence that the beneficial effect of steroids on this outcome has not been exaggerated by selective outcome reporting. ConclusionWe conclude that the evidence that steroids reduce respiratory distress syndrome is secure.

Balancing Demand for Universally Improved Health Outcomes with Need for a Local Standard of Care.

The United States, along with other resource-rich countries, leads global health care by advancing medical care through randomized controlled trials (RCTs). While most medical research is conducted in these resource-rich areas, RCTs, including replications of previous trials, are additionally carried out in low- and middle-income countries. On the basis of positive findings from several RCTs conducted in high-income countries, the Antenatal Corticosteroids Trial (ACT) evaluated the effectiveness of antenatal corticosteroids in reducing neonatal mortality in low- and middle-income countries. ACT, however, was undertaken in dramatically different health care infrastructures and did not confirm the results of previous studies. We argue that it is neither clinically appropriate nor ethically acceptable to extrapolate findings from one region to another without accounting for the disparate cultural values, goals of care, and health services infrastructure that impact clinical outcomes.

17: Antenatal late preterm steroids: a cost analysis

To compare costs of treatment with antenatal corticosteroids versus no treatment for women at risk for late preterm delivery. This is a cost-minimization analysis of a multicenter randomized trial of antenatal corticosteroids versus placebo for women at risk for late preterm delivery. The analysis took a third-party payer approach with a time horizon to first hospital discharge to home. Maternal costs were based on Medicaid rates and included those of the betamethasone (BMZ), as well as the outpatient visits or inpatient stay required to administer the medication (Table). We included all direct medical costs for newborn care. For infants admitted to the NICU, we employed comprehensive daily costs from a similar institution, stratified by the acuity of respiratory illness (ventilator or continuous positive airway pressure (CPAP); Table). For infants admitted to the regular newborn nursery, we used nationally representative estimates from the literature. Maternal and neonatal costs were estimated by treatment assignment, BMZ or placebo and reported in 2015 US$. For this analysis costs were determined from data available for 1425 mother-infant pairs in the BMZ group and 1396 mother-infant pairs in the placebo group. Treatment with BMZ for women at risk for late preterm birth resulted in a total mean cost ($4776.08±$5769.40) that was significantly less than that ($5472.90±$8392.48, p<0.0001) for women who were randomized to placebo (i.e, who did not receive BMZ). Administration of antenatal BMZ to women at risk of late preterm birth significantly decreased health care costs.

Detection and risk stratification of women at high risk of preterm birth in rural communities near Nagpur, India

BackgroundPresently, preterm birth is globally the leading cause of neonatal mortality. Prompt community based identification of women at high risk for preterm births (HRPB) can either help to avert preterm births or avail effective interventions to reduce neonatal mortality due to preterm births. We evaluated the performance of a package to train community workers to detect the presence of signs or symptoms of HRPB.MethodsPregnant women enrolled in the intervention arm of a cluster randomized trial of Antenatal Corticosteroids (ACT Trial) conducted at Nagpur, India were informed about 4 directly observable signs and symptoms of preterm labor. Community health workers actively monitored these women from 24 to 36 weeks of gestation for these signs or symptoms. If they were present (HRPB positive) the identified women were brought to government health facilities for assessment and management. HRPB positive could also be determined by the provider if the woman presented directly to the facility. Risk stratification was based on the number of signs or symptoms present. The outcome of preterm birth was based on the clinical assessment of gestational age < 37 weeks at delivery or a birth weight of <2000 g.ResultsBetween July 1, 2012 and 30 November, 2013, 686 of 7050 (9.7%) pregnant women studied, delivered preterm. 732 (10.4%) women were HRPB positive, of whom 333 (45.5%) delivered preterm. Of the remaining 6318(89.6%) HRPB negative women 353 (5.6%) delivered preterm. The likelihood ratio (LR) of a preterm birth in the HRPB positives was 8.14 (95% confidence interval 7.16–9.26). The LR of a preterm birth increased in women who had more signs or symptoms of HRBP (p < 0.00001). More signs or symptoms of HRPB were also associated with a shorter time to delivery, lower birth weight and higher rates of stillbirths, neonatal deaths and postnatal complications. Addition of risk stratification improved the prediction of preterm delivery (Integrated Discrimination Improvement 17% (95% CI 15–19%)).ConclusionsThe package for detection of signs and symptoms of HRPB is feasible, promising and likely to improve management of preterm labor.Trial registrationNCT01073475 on February 21, 2010 and NCT01084096 on March 9, 2010.

The global network antenatal corticosteroids trial: impact on stillbirth

BackgroundAntenatal corticosteroids are commonly used to reduce neonatal mortality, but most research to date has been in high-resource settings and few studies have evaluated its impact on stillbirth. In the Antenatal Corticosteroids Trial (ACT), a multi-country trial to assess impact of a multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth, we found an overall increase in 28-day neonatal mortality and stillbirth associated with the intervention.MethodsThe ACT was a cluster-randomized trial conducted in 102 clusters across 7 research sites in 6 countries (India [2 sites], Pakistan, Zambia, Kenya, Guatemala and Argentina), comparing an intervention to train birth attendants at all levels of the health system to identify women at risk of preterm birth, administer corticosteroids and refer women at risk. Because of inadequate gestational age dating, the <5th percentile birth weight was used as a proxy for preterm birth. A pre-specified secondary outcome of the trial was stillbirth.ResultsAfter adjusting for the pre-trial imbalance in stillbirth rates, the ACT intervention was associated with a non-significant increased risk of stillbirth (aRR 1.08, 95 % CI, 0.99–1.17, p–0.073). Additionally, the stillbirth rate was higher in the term births (1.20 95 % CI 1.06–1.37, 0.004) and among those with signs of maceration (RR 1.18 (1.04–1.35), p = 0.013) in the intervention vs. control clusters. Differences in obstetric care favored the control clusters and maternal infection was likely more common in the intervention clusters.ConclusionsIn this pragmatic trial, limited data were available to identify the causes of the increase in stillbirths in the intervention clusters. A higher rate of stillbirth in the intervention clusters prior to the trial, differences in obstetric care and an increase in maternal infection are potential explanations for the observed increase in stillbirths in the intervention clusters during the trial.Trial registrationclinicaltrials.gov (NCT01084096)

Use of antenatal corticosteroids at health facilities and communities in low-and-middle income countries.

BackgroundAntenatal corticosteroids (ACS) for women at high risk of preterm birth is an effective intervention to reduce neonatal mortality among preterm babies delivered in hospital settings, but has not been widely used in low-middle resource settings. We sought to assess the rates of ACS use at all levels of health care in low and middle income countries (LMIC).MethodsWe assessed rates of ACS in 7 sites in 6 LMIC participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Global Network for Women and Children’s Health Research Antenatal Corticosteroids Trial (ACT), a cluster-randomized trial to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of ACS. We conducted this analysis using data from the control clusters, which did not receive any components of the intervention and intended to follow usual care. We included women who delivered an infant with a birth weight <5th percentile, a proxy for preterm birth, and were enrolled in the Maternal Newborn Health (MNH) Registry between October 2011 and March 2014 in all clusters. A survey of the site investigators regarding existing policies on ACS in health facilities and for health workers in the community was part of pre-trial activities.ResultsOverall, of 51,523 women delivered in control clusters across all sites, the percentage of <5th percentile babies ranged from 3.5 % in Kenya to 10.7 % in Pakistan. There was variation among the sites in the use of ACS at all hospitals and among those hospitals having cesarean section and neonatal care capabilities (bag and mask and oxygen or mechanical ventilation). Rates of ACS use for <5th percentile babies in all hospitals ranged from 3.8 % in the Kenya sites to 44.5 % in the Argentina site, and in hospitals with cesarean section and neonatal care capabilities from 0 % in Zambia to 43.5 % in Argentina. ACS were rarely used in clinic or home deliveries at any site. Guidelines for ACS use at all levels of the health system were available for most of the sites.ConclusionOur study reports an overall low utilization of ACS among mothers of <5th percentile infants in hospital and clinic deliveries in LMIC.Trial Registrationclinicaltrials.gov (NCT01084096)

The Antenatal Corticosteroids Trial (ACT): a secondary analysis to explore site differences in a multi-country trial.

BackgroundThe Antenatal Corticosteroid Trial (ACT) assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but had no overall impact on neonatal mortality in the targeted <5th percentile birth weight infants. Being in the intervention clusters was also associated with an overall increase in neonatal deaths. We sought to explore plausible pathways through which this intervention increased neonatal mortality.MethodsWe conducted secondary analyses to assess site differences in outcome and potential explanations for the differences in outcomes if found. By site, and in the intervention and control clusters, we evaluated characteristics of the mothers and care systems, the proportion of the <5th percentile infants and the overall population that received ACS, the rates of possible severe bacterial infection (pSBI), determined from clinical signs, and neonatal mortality rates.ResultsThere were substantial differences between the sites in both participant and health system characteristics, with Guatemala and Argentina generally having the highest levels of care. In some sites there were substantial differences in the health system characteristics between the intervention and control clusters. The increase in ACS in the intervention clusters was similar among the sites. While overall, there was no difference in neonatal mortality among <5th percentile births between the intervention and control clusters, Guatemala and Pakistan both had significant reductions in neonatal mortality in the <5th percentile infants in the intervention clusters. The improvement in neonatal mortality in the Guatemalan site in the <5th percentile infants was associated with a higher level of care at the site and an improvement in care in the intervention clusters. There was a significant increase overall in neonatal mortality in the intervention clusters compared to the control. Across sites, this increase in neonatal mortality was statistically significant and most apparent in the African sites. This increase in neonatal mortality was accompanied by a significant increase in pSBI in the African sites.ConclusionsThe improvement in neonatal mortality in the Guatemalan site in the <5th percentile infants was associated with a higher level of care and an improvement in care in the intervention clusters. The increase in neonatal mortality in the intervention clusters across all sites was largely driven by the poorer outcomes in the African sites, which also had an increase in pSBI in the intervention clusters. We emphasize that these results come from secondary analyses. Additional prospective studies are needed to assess the effectiveness and safety of ACS on neonatal health in low resource settings.Trial registrationTrial registration: clinicaltrials.gov (NCT01084096)

Reducing neonatal mortality associated with preterm birth: gaps in knowledge of the impact of antenatal corticosteroids on preterm birth outcomes in low-middle income countries.

The Global Network’s Antenatal Corticosteroids Trial (ACT), was a multi-country, cluster-randomized trial to improve appropriate use of antenatal corticosteroids (ACS) in low-resource settings in low-middle income countries (LMIC). ACT substantially increased ACS use in the intervention clusters, but the intervention failed to show benefit in the targeted < 5th percentile birth weight infants and was associated with increased neonatal mortality and stillbirth in the overall population. In this issue are six papers which are secondary analyses related to ACT that explore potential reasons for the increase in adverse outcomes overall, as well as site differences in outcomes. The African sites appeared to have increased neonatal mortality in the intervention clusters while the Guatemalan site had a significant reduction in neonatal mortality, perhaps related to a combination of ACS and improving obstetric care in the intervention clusters. Maternal and neonatal infections were increased in the intervention clusters across all sites and increased infections are a possible partial explanation for the increase in neonatal mortality and stillbirth in the intervention clusters, especially in the African sites. The analyses presented here provide guidance for future ACS trials in LMIC. These include having accurate gestational age dating of study subjects and having care givers who can diagnose conditions leading to preterm birth and predict which women likely will deliver in the next 7 days. All study subjects should be followed through delivery and the neonatal period, regardless of when they deliver. Clearly defined measures of maternal and neonatal infection should be utilized. Trials in low income country facilities including clinics and those without newborn intensive care seem to be of the highest priority.

The Antenatal Corticosteroids Trial (ACT)'s explanations for neonatal mortality - a secondary analysis.

BackgroundThe Antenatal Corticosteroid Trial assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but was associated with an overall increase in neonatal deaths. We aimed to explore plausible pathways through which this intervention increased neonatal mortality.MethodsWe conducted a series of secondary analyses to assess whether ACS or other components of the multifaceted intervention that might have affected the quality of care contributed to the increased mortality observed: 1) we compared the proportion of neonatal deaths receiving ACS between the intervention and control groups; 2) we compared the antenatal and delivery care process in all births between groups; 3) we compared the rates of possible severe bacterial infection between groups; and 4) we compared the frequency of factors related to ACS administration or maternal high risk conditions at administration between the babies who died and those who survived 28 days among all births in the intervention group identified as high risk for preterm birth and received ACS.ResultsThe ACS exposure among the infants who died up to 28 days was 29 % in the intervention group compared to 6 % in controls. No substantial differences were observed in antenatal and delivery care process between groups. The risk of pSBI plus neonatal death was significantly increased in intervention clusters compared to controls (2.4 % vs. 2.0 %, adjusted RR 1.17, 95 % CI 1.04–1.30, p = 0.008], primarily for infants with birth weight at or above the 25th percentile. Regarding factors related to ACS administration, term infants who died were more likely to have mothers who received ACS within 7 days of delivery compared to those who survived 28 days (26.5 % vs 17.9 %, p = 0.014), and their mothers were more likely to have been identified as high risk for hypertension and less likely for signs of preterm labor.ConclusionsThese results suggest that ACS more than other components of the intervention may have contributed to the overall increased neonatal mortality. ACS may have also been involved in the observed increased risk of neonatal infection and death. Further trials are urgently needed to clarify the effectiveness and safety of ACS on neonatal health in low resource settings.

Antenatal corticosteroids 40 years on: we can do better

In 1972, Liggins and Howie 1 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 Crossref PubMed Google Scholar reported results of their landmark randomised controlled trial of antenatal corticosteroids for the prevention of respiratory distress syndrome associated with preterm birth. That trial provided clear evidence for the drug's efficacy to reduce respiratory distress syndrome and mortality in the 1218 infants enrolled. 2 Dalziel SR Walker NK Parag V et al. Cardiovascular risk factors after exposure to antenatal betamethasone: 30-year follow-up of a randomised controlled trial. Lancet. 2005; 365: 1856-1862 Summary Full Text Full Text PDF PubMed Scopus (340) Google Scholar However, it was not until the publication of a consensus statement by the US National Institutes of Health 3 Gilstrap LC Christensen R Clewell WH et al. The effect of antenatal steroids for fetal maturation on perinatal outcomes-interim draft statement. NIH Consens Statement Online. 1994; 12: 1-24 Google Scholar (22 years and 12 trials later, involving an additional 2138 infants), that this simple and cost-effective treatment was widely adopted. This delay was highlighted by the Cochrane Collaboration who chose the systematic review of antenatal corticosteroids as their logo, emphasising that thousands of preterm infants would not have suffered or died unnecessarily had the available evidence been adopted earlier. 4 Reynolds LA Tansey EM Prenatal corticosteroids for reducing morbidity and mortality after preterm birth. Wellcome Witnesses to Twentieth Century Medicine. volume 25. Wellcome Trust Centre for the History of Medicine at UCL, London2005 Google Scholar Now, however, 40 years after publication of the original trial, there is still debate about the use of antenatal corticosteroids, this time in low-income and middle-income countries. 5 Azad K Costello A Extreme caution is needed before scale-up of antenatal corticosteroids to reduce preterm deaths in low-income settings. Lancet Glob Health. 2014; 2: e191-e192 Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar Use of antenatal corticosteroids and tocolytic drugs in preterm births in 29 countries: an analysis of the WHO Multicountry Survey on Maternal and Newborn HealthUse of interventions was generally poor, despite evidence for their benefit for newborn babies. A substantial proportion of antenatal corticosteroid use occurred at gestational ages at which benefit is controversial, and use of less effective or potentially harmful tocolytic drugs was common. Implementation research and contextualised health policies are needed to improve drug availability and increase compliance with best obstetric practice. Full-Text PDF

Antenatal corticosteroids trial in preterm births to increase neonatal survival in developing countries: study protocol.

BackgroundPreterm birth is a major cause of neonatal mortality, responsible for 28% of neonatal deaths overall. The administration of antenatal corticosteroids to women at high risk of preterm birth is a powerful perinatal intervention to reduce neonatal mortality in resource rich environments. The effect of antenatal steroids to reduce mortality and morbidity among preterm infants in hospital settings in developed countries with high utilization is well established, yet they are not routinely used in developing countries. The impact of increasing antenatal steroid use in hospital or community settings with low utilization rates and high infant mortality among premature infants due to lack of specialized services has not been well researched. There is currently no clear evidence about the safety of antenatal corticosteroid use for community-level births.MethodsWe hypothesize that a multi country, two-arm, parallel cluster randomized controlled trial to evaluate whether a multifaceted intervention to increase the use of antenatal corticosteroids, including components to improve the identification of pregnancies at high risk of preterm birth and providing and facilitating the appropriate use of steroids, will reduce neonatal mortality at 28 days of life in preterm newborns, compared with the standard delivery of care in selected populations of six countries. 102 clusters in Argentina, Guatemala, Kenya, India, Pakistan, and Zambia will be randomized, and around 60,000 women and newborns will be enrolled. Kits containing vials of dexamethasone, syringes, gloves, and instructions for administration will be distributed. Improving the identification of women at high risk of preterm birth will be done by (1) diffusing recommendations for antenatal corticosteroids use to health providers, (2) training health providers on identification of women at high risk of preterm birth, (3) providing reminders to health providers on the use of the kits, and (4) using a color-coded tape to measure uterine height to estimate gestational age in women with unknown gestational age. In both intervention and control clusters, health providers will be trained in essential newborn care for low birth weight babies. The primary outcome is neonatal mortality at 28 days of life in preterm infants.Trial registrationClinicalTrials.gov. Identifier: NCT01084096