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Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

ABSTRACT: BACKGROUND:Antenatal corticosteroids have been proven to prevent adverse outcomes including respiratory morbidities in preterm neonates before 34?weeks of gestation. Recently, it has been suggested that antenatal corticosteroids may also be effective in singleton late preterm pregnancies, and guidelines recommend the use of corticosteroids in singleton pregnant women who are at risk for late preterm birth. On the contrary, there is a paucity of information regarding the effectiveness of corticosteroids in twin neonates with late preterm birth. This study aims to determine the effectiveness of antenatal corticosteroids in late preterm twin neonates. METHODS:In this multicentre randomized controlled trial, women who are at risk for late preterm birth will be enrolled at 34 0/7 to 36 5/7?weeks of gestation. The participants will be randomly assigned to receive antenatal corticosteroids (betamethasone 12?mg, 3?mL intramuscularly [IM]) or placebo (normal saline 3?mL IM). The perinatal outcomes will be compared between the two groups of cases. The primary outcome is severe respiratory complications (the use of continuous positive airway pressure or high-flow nasal cannula for at least 12?h, supplemental oxygen administration with a fraction of oxygen 0.3 or more for at least 24?h, mechanical ventilation, or extracorporeal membranes oxygenation) or perinatal death within the first 72?h of delivery. The secondary outcomes are neonatal mortality and/or other neonatal morbidities. DISCUSSION:This study will be the first randomized controlled trial that evaluates the effectiveness of antenatal corticosteroids in late preterm twin neonates. TRIAL REGISTRATION:NCT03547791 (ClinicalTrials.gov), first submitted date: March 29, 2018, first posted date: June 6, 2018 (retrospectively registered).

SUBMITTER: Hong S

PROVIDER: S-EPMC6446272 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

Hong Subeen S Lee Seung Mi SM Kwak Dong Wook DW Lee Joongyub J Kim So Yeon SY Oh Jeong Won JW Oh Sohee S Park Chan-Wook CW Park Joong Shin JS Chung Jin Hoon JH Jun Jong Kwan JK

BMC pregnancy and childbirth 20190403 1

<h4>Background</h4>Antenatal corticosteroids have been proven to prevent adverse outcomes including respiratory morbidities in preterm neonates before 34 weeks of gestation. Recently, it has been suggested that antenatal corticosteroids may also be effective in singleton late preterm pregnancies, and guidelines recommend the use of corticosteroids in singleton pregnant women who are at risk for late preterm birth. On the contrary, there is a paucity of information regarding the effectiveness of ...[more]

PMID: 30943910

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Project description:BackgroundLate preterm steroid administration can induce transient maternal and thus fetal hyperglycemia, which can increase production of fetal insulin and C-peptide. Infants delivered in this setting are subsequently at increased risk for hypoglycemia. Although maternal glycemic control before delivery is a key component of care for parturients with diabetes, this intervention has not been studied in the setting of late preterm steroid administration.ObjectiveThis study aimed to determine the effect of maternal screening for and treatment of hyperglycemia after late preterm steroid administration on fetal C-peptide levels and other metabolic markers.Study designThis was a multicenter, randomized trial (NCT03076775) of nondiabetic parturients with a singleton gestation receiving betamethasone at 34 0/7 weeks to 36 5/7 weeks for anticipated preterm birth. Participants randomized to maternal glycemic control received fasting and 1-hour postprandial or serial intrapartum capillary blood glucose screening with insulin treatment as indicated. Those randomized to expectant management did not receive any glucose screening or treatment. The primary outcome was fetal C-peptide level measured from umbilical cord blood at delivery. Secondary outcomes included other fetal metabolic markers and neonatal hypoglycemia (glucose level <40 mg/dL). Baseline characteristics and outcomes were compared between the groups. We estimated that we would need a sample size of 144 to provide >90% power to show a 1 ng/mL decrease in C-peptide concentration (±1.5 ng/mL) at ⍺=0.05 using a 2-sample t test and 1 interim analysis. After the interim analysis, the trial was stopped for futility.ResultsOf 491 screened parturients, 163 (33%) were deemed eligible and 86 (53%) were randomized to 1 of the treatment groups (June 2017 to February 2021). One person was lost to follow-up because of delivery at another hospital. Baseline characteristics were similar between groups. The median interval from betamethasone administration to delivery was 24 hours (interquartile range, 13-96 hours) and did not differ between groups (P=.82). Most (82%) randomized to maternal glycemic control had hyperglycemia: 80% had at least 1 fasting glucose level >95 mg/dL, 75% had at least one 1-hour postprandial glucose level >140 mg/dL, and 80% had at least 1 intrapartum glucose level >110 mg/dL. In addition, 15% had at least 1 glucose level >180 mg/dL. None had maternal hypoglycemia after insulin treatment. Compared with expectant management, maternal glycemic control did not affect the median fetal C-peptide level (1.02; interquartile range, 0.52-1.85 vs 1.09; interquartile range, 0.61-1.65; P=.97) or other metabolic markers. Maternal glycemic control also did not affect neonatal hypoglycemia (49% vs 51%; P=.83) or other secondary neonatal or maternal outcomes. There was no evidence of effect modification by gestational age or body mass index at randomization, indication for betamethasone, duration from betamethasone to delivery, maternal race or ethnicity, or neonatal sex. In addition, the results were unchanged in a sensitivity analysis using a per-protocol approach.ConclusionMaternal hyperglycemia was observed in most nondiabetic parturients after receiving late preterm betamethasone. However, there was no improvement in fetal metabolic status, neonatal hypoglycemia, or other neonatal or maternal outcomes with maternal glycemic control. Therefore, maternal glucose surveillance and treatment does not seem to be beneficial in nondiabetic parturients receiving late preterm steroids.

Project description:Background Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies. Methods The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics. Discussion The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals. Trial registration Clinicaltrials.gov, NCT04152980, Registered November 6th, 2019

Project description: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.

Project description:BackgroundPreterm birth complications are the leading cause of deaths for children under five years. Antenatal corticosteroids (ACS) are effective at reducing mortality and serious morbidity amongst infants born at <34 weeks gestation. WHO guidelines strongly recommend use of ACS for women at risk of imminent preterm birth where gestational age, imminent preterm birth, and risk of maternal infection can be assessed, and appropriate maternal/newborn care provided. However, coverage remains low in high-burden countries for reasons not previously systematically investigated.MethodsThe bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the Every Newborn Action Plan process. Country workshops involved technical experts to complete the survey tool, which is designed to synthesise and grade health system "bottlenecks", factors that hinder the scale up, of maternal-newborn intervention packages. We used quantitative and qualitative methods to analyse the bottleneck data, combined with literature review, to present priority bottlenecks and actions relevant to different health system building blocks for ACS.ResultsEleven out of twelve countries provided data in response to the ACS questionnaire. Health system building blocks most frequently reported as having significant or very major bottlenecks were health information systems (11 countries), essential medical products and technologies (9 out of 11 countries) and health service delivery (9 out of 11 countries). Bottlenecks included absence of coverage data, poor gestational age metrics, lack of national essential medicines listing, discrepancies between prescribing authority and provider cadres managing care, delays due to referral, and lack of supervision, mentoring and quality improvement systems.ConclusionsAnalysis centred on health system building blocks in which 9 or more countries (>75%) reported very major or significant bottlenecks. Health information systems should include improved gestational age assessment and track ACS coverage, use and outcomes. Better health service delivery requires clarified policy assigning roles by level of care and cadre of provider, dependent on capability to assess gestational age and risk of preterm birth, and the implementation of guidelines with adequate supervision, mentoring and quality improvement systems, including audit and feedback. National essential medicines lists should include dexamethasone for antenatal use, and dexamethasone should be integrated into supply logistics.

Dataset Information

Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

Publications

Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

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