A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials

Abstract

Objective To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials.

Study Design A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother–neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ≥24 weeks' GA.

Results Among 17,912 mother–neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at <31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without.

Conclusions Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately.

Keywords

neonatal benefit - composite endpoint - preterm birth - preterm labor - gestational age - tocolytics

• References

• 1 Blencowe H, Cousens S, Oestergaard MZ. , et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379 (9832): 2162-2172
• 2 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371 (9606): 75-84
• 3 Blencowe H, Cousens S, Chou D. , et al; Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10 (Suppl. 01) S2
• 4 Lawn JE, Cousens S, Zupan J. ; Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: When? Where? Why?. Lancet 2005; 365 (9462): 891-900
• 5 Liu L, Johnson HL, Cousens S. , et al; Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012; 379 (9832): 2151-2161
• 6 Greenough A. Long-term respiratory consequences of premature birth at less than 32 weeks of gestation. Early Hum Dev 2013; 89 (Suppl. 02) S25-S27
• 7 Institute of Medicine Committee on Understanding Premature Birth. Assuring Healthy Outcomes. The National Academies Collection: Reports funded by National Institutes of Health. In: Behrman RE, Butler AS. , eds. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: National Academies Press/National Academy of Sciences; 2007
• 8 Marlow N, Hennessy EM, Bracewell MA, Wolke D. ; EPICure Study Group. Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics 2007; 120 (04) 793-804
• 9 Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet 2012; 379 (9814): 445-452
• 10 World Health Organization. Every Newborn: an action plan to end preventable deaths. 2014. https://www.everynewborn.org/Documents/Full-action-plan-EN.pdf . Accessed October 19, 2016
• 11 National Institute for Health and Care Excellence (NICE). Preterm labour and birth. NICE guideline [NG25]. Published 20 November 2015 www.nice.org.uk/guidance/ng25 . Accessed February 16, 2018
• 12 Smith GN, Walker MC, Ohlsson A, O'Brien K, Windrim R. ; Canadian Preterm Labour Nitroglycerin Trial Group. Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007; 196 (01) 37.e1-37.e8
• 13 Meher S, Alfirevic Z. Choice of primary outcomes in randomised trials and systematic reviews evaluating interventions for preterm birth prevention: a systematic review. BJOG 2014; 121 (10) 1188-1194 , discussion 1195–1196
• 14 European Network for Health Technology Assessment. Endpoints used for relative effectiveness assessment: composite endpoints 2015. http://www.eunethta.eu/sites/5026.fedimbo.belgium.be/files/Endpoints%20used%20for%20Relative%20Effectiveness%20Assessment%20Composite%20endpoints_Amended%20JA1%20Guideline_Final%20Nov%202015_0.pdf . Accessed October 18, 2016
• 15 GSK. NCT02292771: a randomized study comparing the efficacy and safety of retosiban versus atosiban for women in spontaneous preterm labour. 2015. https://www.clinicaltrials.gov/ct2/results?term=NCT02292771 . Accessed October 19, 2016
• 16 GSK. NCT02377466: a phase III efficacy and safety study of intravenous retosiban versus placebo for women in spontaneous preterm labor. 2015. https://www.clinicaltrials.gov/ct2/results?term=NCT02377466 . Accessed October 19, 2016
• 17 Mercer BM, Rabello YA, Thurnau GR. , et al; NICHD-MFMU Network. The NICHD-MFMU antibiotic treatment of preterm PROM study: impact of initial amniotic fluid volume on pregnancy outcome. Am J Obstet Gynecol 2006; 194 (02) 438-445
• 18 Alexander GR, Kogan M, Bader D, Carlo W, Allen M, Mor J. US birth weight/gestational age-specific neonatal mortality: 1995-1997 rates for whites, Hispanics, and blacks. Pediatrics 2003; 111 (01) e61-e66
• 19 Matthews TJ, MacDorman MF, Thoma ME. Infant mortality statistics from the 2013 period linked birth/infant death data set. Natl Vital Stat Rep 2015; 64 (09) 1-30
• 20 US Food and Drug Administration. Advisory Committee for Reproductive Health Drugs. NDA 22–139 Progesterone gel (8%). 2012. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/reproductivehealthdrugsadvisorycommittee/ucm287987.pdf . Accessed October 19, 2016
• 21 Zephyrin LC, Hong KN, Wapner RJ. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units (MFMU) Network. Gestational age-specific risks vs benefits of multicourse antenatal corticosteroids for preterm labor. Am J Obstet Gynecol 2013; 209 (04) 330.e1-330.e7
• 22 van ʼt Hooft J, Duffy JM, Daly M. , et al; Global Obstetrics Network (GONet). A core outcome set for evaluation of interventions to prevent preterm birth. Obstet Gynecol 2016; 127 (01) 49-58
• 23 Combs CA, Garite T, Maurel K, Das A, Porto M. ; Obstetrix Collaborative Research Network. 17-hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2011; 204 (03) 221.e1-221.e8
• 24 Short EJ, Kirchner HL, Asaad GR. , et al. Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system. Arch Pediatr Adolesc Med 2007; 161 (11) 1082-1087
• 25 Hintz SR, Kendrick DE, Stoll BJ. , et al; NICHD Neonatal Research Network. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005; 115 (03) 696-703
• 26 O'Shea TM, Allred EN, Kuban KC. , et al; ELGAN Study Investigators. Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants. J Child Neurol 2012; 27 (01) 22-29
• 27 Rijken M, Stoelhorst GM, Martens SE. , et al. Mortality and neurologic, mental, and psychomotor development at 2 years in infants born less than 27 weeks' gestation: the Leiden follow-up project on prematurity. Pediatrics 2003; 112 (02) 351-358
• 28 Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M. , et al. Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics 2008; 121 (02) e223-e232
• 29 Shah PS, Lui K, Sjörs G. , et al; International Network for Evaluating Outcomes (iNeo) of Neonates. Neonatal outcomes of very low birth weight and very preterm neonates: an international comparison. J Pediatr 2016; 177: 144-152.e6
• 30 Stoll BJ, Hansen NI, Bell EF. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 2015; 314 (10) 1039-1051