Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012

Abstract

Importance: Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.

Objective: To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.

Design, setting, participants: Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012.

Exposures: Extremely preterm birth.

Main outcomes and measures: Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex.

Results: Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation.

Conclusions and relevance: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions.

Trial registration: clinicaltrials.gov Identifier: NCT00063063.

Figure 1

Care practices by birth year for infants born at GA 22–28 weeks 1993–2012. In each graph, circles show the percent of infants born each year who received the practice, a smoothed curve shows the trend, and shading indicates a 95% CI for the curve. Shading is not visible where CIs are close to values on the curve. Percents are among all infants, except that for postnatal steroids percents are among infants who survived > 12 hours as this outcome was not collected for infants who died ≤12 hours of age. Relative risks based on infants of all GA 22–28 weeks are shown for outcomes for which the year-GA interaction was not significant. When the year-GA interaction was significant, graphs and relative risks are shown for each GA in eFigures 1–4. Relative risks for the change per year were adjusted for study center, maternal race/ethnicity, infant GA, SGA, and sex. Total number of infants included [mean (range) per year] in each graph were: antenatal steroids, 34576 [1728 (1214–2022)]; antenatal antibiotics, 34531 [1726 (1210–2020)]; cesarean delivery, 34611 [1730 (1213–2024)]; intubation, 34611 [1730 (1214–2024)]; surfactant, 34599 [1729 (1214–2023)]; postnatal steroids, 30645 [1532 (1036–1802)].

Adjusted RR (95% CI) for the change per year in all infants where year-GA interaction non-significant
Antenatal Steroids	Antenatal Antibiotics	Cesarean Delivery
	1993–1997: 1.14 (1.12–1.15)
(see eFigure 1)	1998–2006: 0.978 (0.976–0.981)	(see eFigure 2)
	2007–2012: 1.019 (1.014–1.023)
Delivery Room Intubation	Surfactant Therapy	Postnatal Steroids
		1993–1996: 1.18 (1.14–1.21)
(see eFigure 3)	(see eFigure 4)	1997–2004: 0.82 (0.81–0.83)
		2005–2012: 1.00 (0.99–1.02)

Figure 2

Neonatal morbidities by birth year for infants born at GA 22–28 weeks 1993–2012. In each graph, circles show the percent of infants born each year diagnosed with the morbidity and a smoothed curve shows the trend. Shading to indicate a 95% CI for each curve is not visible where CIs are close to values on the curve. Percents shown in graphs are among infants of all GA who survived >12 hours with additional restrictions as noted in text and eTable 3. Relative risks based on infants of all GA 22–28 weeks are shown for outcomes for which the year-GA interaction was not significant. When the year-GA interaction was significant, graphs and relative risks are shown for each GA in eFigures 5–8. Relative risks for the change per year were adjusted for study center, maternal race/ethnicity, infant GA, SGA, and sex. Total number of infants included [mean (range) per year] in each graph were: NEC, 30790 [1539 (1035–1809)]; late-onset sepsis, 29252 [1462 (980–1702)]; ICH, 29883 [1494 (1016–1741)]; PVL, 28498 [1424 (769–1744)]; ROP, 24951 [1247 (808–1509)]; BPD, 25000 [1250 (746–1534)].

Adjusted RR (95% CI) for the change per year in all infants where year-GA interaction non-significant
NEC	Late-onset sepsis	Severe ICH
1993–2008: 1.02 (1.01–1.03)	(see eFigure 5)	(see eFigure 6)
2009–2012: 0.94 (0.91–0.98)
PVL	ROP stage 3+	BPD
(see eFigure 7)	1993–2003: 1.02 (1.01–1.03)	(see eFigure 8)
	2004–2012: 0.94 (0.93–0.95)

Figure 3

Survival to discharge by birth year and GA among infants born 1993–2012. In each graph, circles show the percent of infants born each year who survived to discharge, a smoothed curve shows the trend, and shading indicates a 95% CI for the curve. Shading is not visible where CIs are close to values on the curve. Percents are among all infants, including those who died ≤ 12 hours. Relative risks for the change per year were adjusted for study center, maternal race/ethnicity, infant GA, SGA, and sex. Survival trends did not vary significantly by GA from 1993–2008 (year-GA interaction, p=0.46) with no significant change in survival (p=0.90) but varied by GA from 2009–2012 (year-GA interaction, p<0.001). Therefore, relative risks are shown for 2009–2012 only. Total number of infants included [mean (range) per year] in each graph were: 22 weeks, 1550 [77 (48–96)]; 23 weeks, 3133 [156 (122–189)]; 24 weeks, 4762 [238 (151–334)]; 25 weeks, 5361 [268 (170–339)]; 26 weeks, 5829 [291 (182–361)]; 27 weeks, 6627 [331(204–399)]; 28 weeks, 7374 [368 (275–430)].

Adjusted RR (95% CI) for the change per year 2009–2012
22 weeks	23 weeks	24 weeks	25 weeks
1.06 (0.89–1.25)	1.09 (1.05–1.14)	1.05 (1.03–1.07)	1.02 (1.01–1.03)
26 weeks	27 weeks	28 weeks
1.00 (0.996–1.015)	1.01 (1.002–1.016)	1.00 (0.998–1.011)

Figure 4

Survival to discharge without major morbidity among infants who survived to discharge by birth year and GA among infants born 1993–2012. Major morbidity was defined as one or more of necrotizing enterocolitis, infections (early-onset sepsis, late-onset sepsis, or meningitis), BPD, severe ICH, PVL, and ROP stage ≥ 3. In each graph, circles show the percent of infants who survived without major morbidity each year, a smoothed curve shows the trend, and shading indicates a 95% CI for the curve. Percents are among infants who survived to discharge excluding those not adequately evaluated for major morbidity. Infants born at GA 22 weeks are not shown as only 99 of 1550 survived to discharge and only 5 survived without major morbidity. Relative risks for the change per year were adjusted for study center, maternal race/ethnicity, infant GA, SGA, and sex. Trends varied by GA (year-GA interaction p=0.01). Total number of infants included [mean (range) per year] in each graph were: 23 weeks, 877 [43 (33–69)]; 24 weeks, 2706 [135 (75–183)]; 25 weeks, 4007 [200 (119–249)]; 26 weeks, 4900 [245 (155–313)]; 27 weeks, 5902 [295 (184–350)]; 28 weeks, 6808 [340 (256–405)].

Adjusted RR (95% CI) for the change per year
23 weeks	24 weeks	25 weeks
1.00 (0.95–1.05)	0.99 (0.97–1.01)	1.02 (1.01–1.03)
26 weeks	27 weeks	28 weeks
1.02 (1.01–1.03)	1.02 (1.02–1.03)	1.03 (1.02–1.03)