Deaths in a Modern Cohort of Extremely Preterm Infants From the Preterm Erythropoietin Neuroprotection Trial

Abstract

Importance: Understanding why and how extremely preterm infants die is important for practitioners caring for these infants.

Objective: To examine risk factors, causes, timing, and circumstances of death in a modern cohort of extremely preterm infants.

Design, setting, and participants: A retrospective cohort review of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial between December 13, 2013, and September 26, 2016, was conducted. A total of 941 infants born between 24 0/7 and 27 6/7 weeks of gestation enrolled at 19 US sites comprising 30 neonatal intensive care units were included. Data analysis was performed from October 16, 2020, to December 1, 2021.

Main outcomes and measures: Risk factors, proximal causes, timing, and circumstances of in-hospital death.

Results: Of the 941 enrolled infants, 108 died (11%) before hospital discharge: 38% (n = 41) at 24 weeks' gestation, 30% (n = 32) at 25 weeks' gestation, 19% (n = 20) at 26 weeks' gestation, and 14% (n = 15) at 27 weeks' gestation. An additional 9 infants (1%) died following hospital discharge. In descending order, the primary causes of death included respiratory distress or failure, pulmonary hemorrhage, necrotizing enterocolitis, catastrophic intracranial hemorrhage, sepsis, and sudden unexplained death. Fifty percent of deaths occurred within the first 10 days after birth. The risk of death decreased with day of life and postmenstrual age such that an infant born at 24 weeks' gestation who survived 14 days had the same risk of death as an infant born at 27 weeks' gestation: conditional proportional risk of death, 0.08 (95% CI, 0.03-0.13) vs 0.06 (95% CI, 0.01-0.11). Preterm labor was associated with a decreased hazard of death (hazard ratio [HR], 0.45; 95% CI, 0.31-0.66). Infant clinical factors associated with death included birth weight below the tenth percentile for gestational age (HR, 2.11; 95% CI, 1.38-3.22), Apgar score less than 5 at 5 minutes (HR, 2.19; 95% CI, 1.48-3.24), sick appearance at birth (HR, 2.49; 95% CI, 1.69-3.67), grade 2b-3 necrotizing enterocolitis (HR, 7.41; 95% CI, 5.14-10.7), pulmonary hemorrhage (HR, 10.0; 95% CI, 6.76-18.8), severe intracranial hemorrhage (HR, 4.60; 95% CI, 3.24-5.63), and severe sepsis (HR, 4.93; 95% CI, 3.67-7.21). Fifty-one percent of the infants received comfort care before death.

Conclusions and relevance: In this cohort study, an association between mortality and gestational age at birth was noted; however, for each week that an infant survived, their risk of subsequent death approximated the risk observed in infants born 1 to 2 weeks later, suggesting the importance of an infant's postmenstrual age. This information may be useful to include in counseling of families regarding prognosis of survival.

Figure 1.. Percentage of Deaths as a Function of Postnatal Age

The percentage of in-hospital deaths is shown by postnatal age for cohorts born 1989-1991 as reported by Meadow et al and 2000-2011 as reported by Patel et al, compared with the current 2013-2016 cohort from the Preterm Erythropoietin Neuroprotection (PENUT) trial. In the most current cohort, infants survived longer.

Figure 2.. Infant Factors and Serious Adverse Events (SAEs) Associated With Death

Hazard ratios (HRs) for in-hospital death by infant risk factors and common SAEs. Each factor was considered separately, so the HR for each factor represents the result of a separate Cox proportional hazard model. All models were adjusted for treatment group and gestational age at birth. SAEs were assessed as time-varying covariates for risk of death, with the HR adjudicated from the time the SAE occurred. Epo indicates erythropoietin; ICH, intracerebral hemorrhage; NEC, necrotizing enterocolitis; and SIP, spontaneous intestinal perforation. ^aSick appearance at birth was a subjective assessment by the attending neonatologist.

Figure 3.. Cause of Death by Gestational Age

Total deaths (A) and normalized proportion of deaths (B) by gestational age, with proximal cause of death shown. NEC indicates necrotizing enterocolitis; SIP, spontaneous intestinal perforation.

Figure 4.. In-Hospital Deaths by Cause in the Neonatal Period

Timing and proximal cause of death for all neonatal deaths (first 28 days of life) (A) and separated by week of gestation (B). The total number of in-hospital neonatal deaths for each cause of death were respiratory distress syndrome, n = 36; necrotizing enterocolitis (NEC)/intestinal perforation, n = 17; pulmonary hemorrhage, n = 7; intracranial hemorrhage, n = 6; respiratory failure, n = 4; sepsis/meningitis, n = 4; sudden cardiac arrest, n = 4; and other, n = 3.