Abstract
Background
Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease.
Objective
We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks’ postmenstrual age.
Study Design
Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks’ gestational age with a birth weight of 401 g and above born between January 1, 2006, and December 31, 2014 were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks’ postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch.
Results
Infants exposed to any antenatal corticosteroids had a lower rate of death [2193/9670 (22.7%)] compared to infants without exposure [540/1302 (41.5%)]; adjusted relative risk (ARR), 0.71 (95% confidence interval (CI), 0.65 to 0.76; p<0.0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death [654/2520 (26.0%)] compared to infants without exposure [540/1302 (41.5%); ARR, 0.77 (95% CI, 0.70 to 0.85); p<0.0001]. In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23 to 27 weeks’ gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks’ gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure.
Conclusion
Among infants 22–28 weeks’ gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ.
Keywords: Antenatal corticosteroids, bronchopulmonary dysplasia, infant, mortality, morbidity, newborn, preterm, pulmonary, neonatal, respiratory distress syndrome, surfactant, mechanical ventilation, pneumothorax, pulmonary hemorrhage, sepsis, necrotizing enterocolitis, intracranial hemorrhage, periventricular leukomalacia, respiratory support, patent ductus arteriosus
INTRODUCTION
The effects of antenatal corticosteroids on mortality and pulmonary outcomes at the lowest gestations show mixed results, in part due to the small sample size of randomized controlled trials.1,2 Although antenatal corticosteroids are given primarily to induce pulmonary maturity, induce surfactant release, and decrease respiratory distress syndrome, randomized controlled trials and meta-analyses of antenatal corticosteroids show no reduction in respiratory distress syndrome or neonatal death for infants delivered less than 30 weeks’ gestation.1,2 In addition, there are limited data from observational studies comparing the pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids to those without exposure because these studies have not been focused on pulmonary outcomes.3–8 Extremely preterm infants who die before 36 weeks’ postmenstrual age cannot be assessed for the development of bronchopulmonary dysplasia, a type of chronic lung disease which is diagnosed at 36 weeks’ postmenstrual age.9 It is important to evaluate the competing outcomes of bronchopulmonary dysplasia and death both together and separately. Antenatal corticosteroid exposure may affect both outcomes for example if more infants survive following exposure and then develop bronchopulmonary dysplasia subsequently.
A complete course of antenatal corticosteroids is defined as two intramuscular doses of betamethasone given 12 to 24 hours apart or four intramuscular doses of dexamethasone given 12 hours apart.10 Many preterm infants are born prior to the administration of a complete course of antenatal corticosteroids.11,12 There are insufficient data on mortality and pulmonary outcomes of extremely preterm infants born after exposure to either a complete or a partial course of antenatal corticosteroids. We hypothesized that the rates of death would be lower in infants exposed to antenatal corticosteroids. In addition, we hypothesized that the rates of physiologic bronchopulmonary dysplasia or death would be lower in infants exposed to antenatal corticosteroids. This study was also designed to determine if exposure to a partial or a complete course of antenatal corticosteroids is associated with improved survival and pulmonary outcomes in extremely preterm infants.
MATERIALS AND METHODS
This was a hypothesis-driven study using data collected prospectively for the Neonatal Research Network Generic Database and Follow-up studies. These data included infants 22 0/7 to 28 6/7 weeks’ gestation with a birth weight of 401 g and above born between January 1, 2006 and December 31, 2014 at any of the National Institute of Child Health and Human Development Neonatal Research Network centers. Maternal and neonatal socio-demographic and clinical data were collected from medical records by trained research personnel. Gestational age was determined by best obstetric estimate over best neonatal estimate.13 Infants with congenital anomalies were included if they were resuscitated as these infants were less likely to have lethal anomalies. Infants who died in the first 12 hours after birth without delivery room resuscitation were excluded from the primary analysis to ensure that results were not affected by planned restriction of care but were included in a secondary analysis. The study protocol was approved by each center’s institutional review board.
Definitions
Infants were considered exposed to antenatal corticosteroids if their mother had received one or more doses of either betamethasone or dexamethasone.10 Mothers were considered to have received a complete course if they had received at least two doses and 24 hours had passed from the time the first dose of antenatal corticosteroids was given. Data on repeat courses of antenatal corticosteroids were not collected.14 Data were collected using standardized definitions until death or discharge. Follow up data was collected using standardized definitions on eligible surviving infants at 18–22 months corrected gestational age. Bronchopulmonary dysplasia was defined based on respiratory support at 36 weeks’ postmenstrual age using the physiologic definition which uses an oxygen reduction challenge test among eligible infants.15 The physiologic definition has been shown to be more reliable and precise than the clinical definition of bronchopulmonary dysplasia15 (defined as supplemental oxygen at 36 weeks’ postmenstrual age) and has been used by the Neonatal Research Network since 2006. All other outcomes were based on standardized definitions as per the Generic Database of the Neonatal Research Network.16 Cause of death was defined as the underlying proximate disease which initiated the series of events leading to death based on both clinical evidence and autopsy findings where available.13
Statistical Analysis
The primary outcome measure was death before discharge. A formal sample size and power estimate demonstrated that the sample size resulting from inclusion of all infants delivered between January 1, 2006 and December 31, 2014 would provide more than 95% power to detect an absolute difference of 4% centered around an overall event rate of 25%. All secondary outcome measures and analyses were pre-specified. All outcomes were analyzed by level of exposure to antenatal corticosteroid; complete exposure, partial exposure, any (partial or complete) exposure, and no exposure. Differences in categorical variables were described using Fisher’s exact test. Kruskal-Wallis test was used for continuous skewed variables. Robust Poisson regression analysis was performed for factors present at birth associated with pulmonary outcomes including birth weight, sex, multiple births, small for gestational age (less than the 10th centile), maternal variables (age, marital status, race, diabetes, rupture of membranes ≥ 24 hours, antepartum hemorrhage, and mode of delivery), center, and epoch (2006–2009, and 2010–2014).17–19 There were 0.5% missing data for the primary outcome and 9.7% missing data for the follow-up outcomes at 18–22 months corrected gestational age. To ensure that results were not affected by missing data, multiple imputation analyses were additionally conducted for outcomes with more than 1% of data missing, or when there was an imbalance of missing data of more than 0.3% between groups. An additional analysis was also performed adjusting for chorioamnionitis (diagnosed by placental pathology). This separate analysis was not performed by each week of gestation. SAS software version 9.3 (SAS Institute Inc) was used for all statistical analyses. Odds ratios and 95% confidence intervals were estimated for binary outcomes with a two sided p value of less than 0.05 indicating statistical significance.
RESULTS
A total of 11,022 infants met the inclusion criteria of whom 9,715 (88.1%) were exposed to antenatal corticosteroids. The proportion of infants at each gestational age from 23 to 28 weeks exposed to antenatal corticosteroids increased over the study period (Figure 1). Mothers of infants exposed to antenatal corticosteroids were more likely to be White, delivered by cesarean section, with private health insurance. Infants exposed to antenatal corticosteroids had higher birth weight, longer gestational age, and were more likely to be small for gestational age, and the product of multiple births (Table 1).
Figure 1.
Frequency of exposure to antenatal corticosteroids (ANS) by gestational age and year of birth. The administration of antenatal corticosteroids increased over the study period but remained lower at the lower gestational ages.
Table 1.
Infant/maternal baseline characteristics by antenatal corticosteroid treatment
| Any ANS | No ANS | |
|---|---|---|
| Study population, n | 9715 | 1307 |
| Mother | ||
| Maternal race/ethnicity | ||
| Black (including Black Hispanic) | 3893 (40.9)a | 663 (52.0)a |
| White (including White Hispanic) | 5066 (53.3)a | 546 (42.8)a |
| Other | 550 (5.8)a | 66 (5.2)a |
| All Hispanic | 1366 (14.5)a | 288 (22.7)a |
| Maternal health insurance | ||
| Medicaid | 5096 (52.8)a | 807 (62.4)a |
| Private insurance | 4072 (42.2)a | 355 (27.5)a |
| Self-pay/uninsured | 480 (5.0)a | 131 (10.1)a |
| Infant | ||
| Birth weight, g | 748 ± 148a | 719 ± 155a |
| Gestational age, wk | 25.5 ± 1.5a | 24.8 ± 1.7a |
| Male sex | 4731 (48.7) | 668 (51.1) |
| Multiple births | 2565 (26.4)a | 285 (21.8)a |
| Small for gestational age | 1078 (11.1)a | 99 (7.6)a |
| Caesarean delivery | 6697 (68.9)a | 743 (56.9)a |
Values are n (%) or ± SD.
ANS, antenatal corticosteroid.
Significant with P value <.05 for comparisons of ANS vs no ANS data.
Infants exposed to any antenatal corticosteroids had lower mortality before discharge [2193/9670 (22.7%)] compared to infants without exposure [540/1302 (41.5%); adjusted relative risk (ARR), 0.71 (95% CI, 0.65 to 0.76); p<0.0001] (Table 2). Infants exposed to a partial course of antenatal corticosteroids also had lower mortality before discharge compared to infants without exposure (Table S1 in the Supplementary Appendix). In the analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23 to 27 weeks’ gestation (Table 3, Figure 2). Infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks’ gestation (Table 3, Figure 2).
Table 2.
Outcomes of infants by exposure to antenatal corticosteroids
| Any ANS n/total n (%) |
No ANS n/total n (%) |
ARR (95% CI)a | |
|---|---|---|---|
| Total study population | N=9715 | N=1307 | |
| Death | |||
| By 36 wk’ postmenstrual age | 1952/9692 (20.1) | 513/1305 (39.3) | 0.67 (0.62 – 0.73)b |
| Before discharge | 2193/9670 (22.7) | 540/1302 (41.5) | 0.71 (0.65 – 0.76)b |
| Due to bronchopulmonary dysplasia | 172/9661 (1.8) | 16/1299 (1.2) | 1.65 (0.96 – 2.83)c |
| Due to respiratory distress syndrome | 698/9661 (7.2) | 171/1299 (13.2) | 0.72 (0.60 – 0.86)b,c |
| Bronchopulmonary dysplasia (physiologic definition) or death by 36 wk’ postmenstrual age | 6016/9579 (62.8) | 940/1300 (72.3) | 0.94 (0.91 – 0.98)b |
| Population of survivors | N=7477 | N=762 | |
| Bronchopulmonary dysplasia, physiologic definition | 3810/7359 (51.8) | 396/755 (52.5) | 0.96 (0.89 – 1.03) |
| Bronchopulmonary dysplasia, by use of supplemental oxygen at 36 wk’ postmenstrual age, clinical definition | 3999/7431 (53.8) | 415/759 (54.7) | 0.96 (0.90 – 1.03) |
| Respiratory distress syndrome | 7367/7477 (98.5) | 760/762 (99.7) | 0.99 (0.99 – 1.00) |
| Surfactant use | 6347/7477 (84.9) | 702/762 (92.1) | 0.92 (0.89 – 0.94)b |
| Mechanical ventilation | 6742/7472 (90.2) | 723/762 (94.9) | 0.96 (0.94 – 0.98)b |
| Pneumothorax | 354/7477 (4.7) | 45/762 (5.9) | 0.78 (0.56 – 1.08)c |
| Pulmonary hemorrhage | 305/7477 (4.1) | 47/762 (6.2) | 0.75 (0.55 – 1.03)c |
| Treatment with post-natal steroids for bronchopulmonary dysplasia | 1218/7268 (16.8) | 112/733 (15.3) | 0.98 (0.82 – 1.18) |
| Early onset sepsis | 134/7477 (1.8) | 17/762 (2.2) | 0.67 (0.40 – 1.13)c |
| Necrotizing enterocolitis ≥ stage 2 | 668/7476 (8.9) | 71/762 (9.3) | 0.98 (0.77 – 1.26)c |
| Intracranial hemorrhage/periventricular leukomalacia | 1028/7445 (13.8) | 167/761 (21.9) | 0.66 (0.57–0.77)b,c |
| Patent ductus arteriosus treated with indomethacin/ibuprofen | 2454/7471 (32.8) | 293/761 (38.5) | 0.95 (0.86 – 1.05) |
| Retinopathy of prematurity ≥ stage 3 or treated with ablation/anti-VEGF drug | 1325/7342 (18.0) | 178/753 (23.6) | 0.76 (0.66 – 0.87)b,c |
| Respiratory support at discharge, oxygen | 2386/7216 (33.1) | 195/740 (26.4) | 1.17 (1.03 – 1.33)b,c |
| Prolonged hospital stay ≥ 120 d, all causes | 2086/7315 (28.5) | 235/752 (31.3) | 0.94 (0.84 – 1.05) |
| Population of survivors eligible for follow-up | N=4149 | N=471 | |
| Respiratory support at 18–22 mo corrected age, ventilation/CPAP | 67/3749 (1.8) | 7/422 (1.7) | 0.91 (0.42 – 1.99)c |
| Oxygen at 18–22 mo corrected age | 201/3749 (5.4) | 20/422 (4.7) | 1.01 (0.65 – 1.58)c |
ANS, antenatal corticosteroid; ARR, adjusted relative risk; CI, confidence interval; CPAP, continuous positive airway pressure; VEGF, vascular endothelial growth factor.
ARR and 95% CI are estimated with no ANS (not exposed to ANS) group used as referent category except for complete vs partial column where ARR and 95%CI are expressed for complete course of ANS compared to partial course of ANS-models adjust for birthweight, sex, multiple births, small for gestational age, maternal variables (age, marital status, race, diabetes, rupture of membranes >24 h, antepartum hemorrhage, and mode of delivery), center, and epoch
Significant with P value <.05
Model does not adjust for center-model did not converge with center included.
Table 3.
Selected outcomes of infants 22–28 weeks’ gestation by antenatal corticosteroid treatment for births from 2006 through 2014
| Complete ANS | Partial ANS | No ANS | |||
|---|---|---|---|---|---|
| n/total n (%) | ARR (95% CI)a | n/total n (%) | ARR (95% CI) | n/total n (%) | |
| Bronchopulmonary dysplasia, physiologic, or death by 36 wk’ postmenstrual age | |||||
| 22 wk | 45/48 (93.8) | 0.95 (0.86–1.05) | 27/28 (96.4) | 0.96 (0.88–1.05) | 94/96 (97.9) |
| 23 wk | 437/508 (86.0) | 0.89 (0.84–0.94)b | 282/312 (90.4) | 0.98 (0.93–1.02) | 264/281 (94.0) |
| 24 wk | 1100/1390 (79.1) | 0.95 (0.87–1.03) | 404/499 (81.0) | 1.03 (0.94–1.12) | 166/208 (79.8) |
| 25 wk | 1043/1581 (66.0) | 0.93 (0.84–1.02)c | 374/572 (65.4) | 0.94 (0.84–1.05) | 163/250 (65.2) |
| 26 wk | 835/1483 (56.3) | 0.93 (0.83–1.04)c | 283/495 (57.2) | 0.97 (0.84–1.11) | 144/245 (58.8) |
| 27 wk | 592/1243 (47.6) | 0.86 (0.72–1.02)c | 159/367 (43.3) | 0.84 (0.69–1.03)c | 74/132 (56.1) |
| 28 wk | 330/781 (42.3) | 0.98 (0.75–1.27)c | 85/231 (36.8) | 0.88 (0.64–1.20)c | 35/88 (39.8) |
| Death by 36 wk’ postmenstrual age | |||||
| 22 wk | 31/48 (64.6) | 0.79 (0.61–1.04)c | 19/29 (65.5) | 0.85 (0.64–1.14)c | 78/97 (80.4) |
| 23 wk | 226/509 (44.4) | 0.68 (0.59–0.78)b,c | 156/314 (49.7) | 0.77 (0.67–0.88)b,c | 194/281 (69.0) |
| 24 wk | 441/1409 (31.3) | 0.54 (0.45–0.64)b,c | 170/504 (33.7) | 0.75 (0.60–0.93)b | 99/209 (47.4) |
| 25 wk | 310/1596 (19.4) | 0.66 (0.51–0.85)b,c | 122/576 (21.2) | 0.76 (0.58–0.99)b,c | 68/253 (26.9) |
| 26 wk | 176/1499 (11.7) | 0.55 (0.40–0.76)b,c | 69/499 (13.8) | 0.64 (0.45–0.92)b,c | 47/247 (19.0) |
| 27 wk | 112/1262 (8.9) | 0.60 (0.37–0.98)b,c | 37/372 (9.9) | 0.73 (0.42–1.27)c | 20/130 (15.4) |
| 28 wk | 56/796 (7.0) | 0.82 (0.39–1.74)c | 18/233 (7.7) | 0.75 (0.30–1.87)c | 7/88 (8.0) |
| Death before discharge | |||||
| 22 wk | 32/48 (66.7) | 0.83 (0.64–1.07)c | 19/29 (65.5) | 0.83 (0.63–1.10)c | 79/96 (82.3) |
| 23 wk | 243/505 (48.1) | 0.72 (0.63–0.82)b,c | 164/310 (52.9) | 0.80 (0.70–0.91)b,c | 199/280 (71.1) |
| 24 wk | 480/1406 (34.1) | 0.57 (0.48–0.67)b,c | 184/504 (36.5) | 0.75 (0.61–0.91)b | 105/207 (50.7) |
| 25 wk | 352/1592 (22.1) | 0.75 (0.59–0.95)b,c | 136/574 (23.7) | 0.83 (0.64–1.07)c | 71/253 (28.1) |
| 26 wk | 210/1498 (14.0) | 0.61 (0.45–0.82)b,c | 78/499 (15.6) | 0.67 (0.48–0.94)b,c | 51/247 (20.6) |
| 27 wk | 138/1260 (11.0) | 0.58 (0.38–0.87)b,c | 47/371 (12.7) | 0.70 (0.44–1.13)c | 26/131 (19.8) |
| 28 wk | 74/795 (9.3) | 0.86 (0.44–1.67)c | 26/233 (11.2) | 1.06 (0.49–2.27)c | 9/88 (10.2) |
| Bronchopulmonary dysplasia, physiologic definition | |||||
| 22 wk | 13/16 (81.3) | 0.64 (0.35–1.16) | 8/9 (88.9) | 0.96 (0.82–1.11)c | 15/16 (93.8) |
| 23 wk | 191/261 (73.2) | 0.80 (0.68–0.94)b,c | 114/144 (79.2) | 0.97 (0.83–1.12)c | 64/81 (79.0) |
| 24 wk | 619/907 (68.2) | 1.09 (0.92–1.30)c | 220/315 (69.8) | 1.18 (0.98–1.41) | 59/101 (58.4) |
| 25 wk | 690/1224 (56.4) | 0.96 (0.83–1.12)c | 235/434 (54.1) | 0.95 (0.81–1.12) | 92/179 (51.4) |
| 26 wk | 622/1268 (49.1) | 0.99 (0.85–1.15)c | 206/417 (49.4) | 0.95 (0.80–1.12)c | 93/194 (47.9) |
| 27 wk | 454/1103 (41.2) | 0.94 (0.74–1.19)c | 111/319 (34.8) | 0.87 (0.66–1.15)c | 47/105 (44.8) |
| 28 wk | 258/706 (36.5) | 1.02 (0.74–1.42)c | 59/205 (28.8) | 0.83 (0.56–1.22)c | 26/79 (32.9) |
| Respiratory support at discharge, oxygen | |||||
| 22 wk | 13/16 (81.3) | d | 6/10 (60.0) | 0.52 (0.23–1.18)c | 9/14 (64.3) |
| 23 wk | 150/258 (58.1) | 1.04 (0.78–1.39)c | 82/140 (58.6) | d | 36/77 (46.8) |
| 24 wk | 407/892 (45.6) | 1.26 (0.94–1.69)c | 134/309 (43.4) | 1.17 (0.86–1.60)c | 34/101 (33.7) |
| 25 wk | 434/1196 (36.3) | 1.06 (0.83–1.36)c | 158/431 (36.7) | 1.22 (0.92–1.60)c | 50/179 (27.9) |
| 26 wk | 352/1238 (28.4) | 1.21 (0.90–1.62)c | 124/409 (30.3) | 1.23 (0.90–1.68)c | 44/191 (23.0) |
| 27 wk | 278/1077 (25.8) | 1.39 (0.90–2.13)c | 63/317 (19.9) | 1.22 (0.74–2.03)c | 18/101 (17.8) |
| 28 wk | 144/688 (20.9) | 3.62 (1.38–9.46)c | 38/202 (18.8) | d | 4/77 (5.2) |
ANS, antenatal corticosteroid; ARR, adjusted relative risk; CI, confidence interval.
ARR and 95% CI are estimated with no ANS (not exposed to ANS) group used as referent category-models adjust for birthweight, sex, multiple births, small for gestational age, maternal variables (age, marital status, race, diabetes, rupture of membranes >24 h, antepartum hemorrhage, and mode of delivery), center, and epoch
Significant with P value <.05
Model does not adjust for center-model did not converge with center included
Model did not converge even with center excluded-for respiratory support at discharge (oxygen): unadjusted relative risks (95% CI) for complete ANS at 22 wk: 1.26 (0.80-1.99); for partial ANS at 23 wk: 1.25 (0.95-1.65); and for partial ANS at 28 wk: 3.62 (1.34-9.81).
Figure 2.
Death before discharge of infants 22 to 28 weeks’ gestation by antenatal corticosteroid (ANS) exposure. Infants exposed to a course of antenatal corticosteroids had a lower rate of death before discharge compared to infants who were not exposed to antenatal corticosteroids at each gestational age from 23 to 27 weeks. Infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks’ gestation.
Infants exposed to any antenatal corticosteroids had a lower rate of physiologic bronchopulmonary dysplasia or death by 36 weeks’ postmenstrual age [6,016/9,579 (62.8%)] compared to infants without exposure [940/1,300 (72.3%)]; ARR, 0.94 (95% CI, 0.91 to 0.98); p=0.001] (Table 2). The rate of physiologic bronchopulmonary dysplasia or death by 36 weeks’ postmenstrual age did not differ among infants exposed to a partial course of antenatal corticosteroids compared to infants without exposure (Table S1 in the Supplementary Appendix). The rate of physiologic bronchopulmonary dysplasia among survivors at 36 weeks’ postmenstrual age did not differ significantly in infants exposed to any antenatal corticosteroids compared to infants without exposure (Table 2). The rate of death due to bronchopulmonary dysplasia did not differ significantly in infants exposed to any antenatal corticosteroids [172/9661 (1.8%)] compared to infants without exposure [16/1299 (1.2%)]; ARR, 1.65 (95% CI, 0.96 to 2.83); p=0.068].
The rate of respiratory distress syndrome did not differ in infants exposed to any antenatal corticosteroids compared to infants without exposure (Table 2). The rate of death due to respiratory distress syndrome was lower in infants exposed to any antenatal corticosteroids compared to infants without exposure (Table 2). The rate of death due to respiratory distress syndrome was also lower in infants exposed to a complete or partial course of antenatal corticosteroids compared to infants without exposure (Table S1 in Supplementary Appendix). The rate of surfactant use and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure (Table 2).
Infants exposed to any antenatal corticosteroids had a lower rate of severe intracranial hemorrhage/periventricular leukomalacia and severe retinopathy of prematurity compared to infants without exposure (Table 2). The rate of pulmonary hemorrhage, pneumothorax, early onset sepsis, proven necrotizing enterocolitis, patent ductus arteriosus treated with indomethacin/ibuprofen, treatment with postnatal steroids for bronchopulmonary dysplasia, and prolonged hospital stay did not differ by antenatal corticosteroids exposure (Table 2). Among survivors exposed to any antenatal corticosteroids there was a higher rate of oxygen therapy at discharge compared to infants without exposure but among survivors who were followed at 18–22 months’ corrected age, the rate of oxygen therapy and continuous positive airway pressure/ventilator did not differ by antenatal corticosteroid exposure (Table 2).
Infants exposed to a complete course of antenatal corticosteroids had a lower rate of death before discharge compared to infants exposed to a partial course of antenatal corticosteroids (Table S1 in the Supplementary Appendix). Infants exposed to a complete course of antenatal corticosteroids also had a lower rate of death due to respiratory distress syndrome, surfactant use, mechanical ventilation, severe intracranial hemorrhage/periventricular leukomalacia, and pulmonary hemorrhage compare to infants exposed to a partial course of antenatal corticosteroids (Table S1 in the Supplementary Appendix).
The inclusion of the 883 infants who died within 12 hours without receiving delivery room resuscitation strengthened the association between lower mortality and exposure to antenatal corticosteroids, particularly among infants at the lowest gestations (Table S2 in the Supplementary Appendix). The results of the models using multiple imputation for missing data were substantively similar to the primary analysis (Table S3 in the Supplementary Appendix). The results of the models that included chorioamnionitis did not substantively differ and are not presented.
COMMENT
Principal Findings
This large multicenter observational study shows that exposure to a complete or partial course of antenatal corticosteroids is associated with lower mortality in infants 22 to 28 weeks’ gestation and weighing 401 grams and above after adjustment for multiple confounders. Among survivors, the rate of bronchopulmonary dysplasia in infants exposed to either a complete or partial course of antenatal corticosteroids did not differ compared to infants who were not exposed. Although all groups had a high rate of respiratory distress syndrome, there was a lower rate of death due to respiratory distress syndrome and a lower use of surfactant and mechanical ventilation among infants exposed to antenatal corticosteroids indicating amelioration of the course of respiratory distress syndrome.
Meaning/clinical implications of findings
The current study demonstrates a lower rate of death associated with exposure to antenatal corticosteroids in infants less than 29 weeks’ gestation. Randomized controlled trials of administration of antenatal corticosteroids to women who delivered at less than 30 weeks’ gestation show inconclusive neonatal outcomes, in part due to small sample size.1–2 In the Cochrane review subgroup analysis of those infants less than 28 weeks’ gestation, there was no significant reduction in the rate of neonatal death but the sample was small [two studies, 89 infants]. The current study agrees with data from observational studies which show a survival benefit among extremely preterm infants at the lowest gestations.20
Many of the studies included in the meta-analyses of randomized controlled trials1–2 were carried out in the era before the widespread use of surfactant and when the methods of ventilatory support used were different.21–22 In the Cochrane review subgroup analysis of those infants less than 28 weeks’ gestation, there was no significant reduction in the rate of respiratory distress syndrome [four studies, 102 infants].1 Rates of bronchopulmonary dysplasia were not analyzed by gestational age at delivery but were not different for the cohort as a whole [six studies, 818 infants]. In the current study, the rates of respiratory distress syndrome and the rates of bronchopulmonary dysplasia among survivors were also not different.
Observational studies have shown marked variability in pulmonary outcomes in infants at the lowest gestations. A NICHD Neonatal Research Network study including 10,541 infants delivered between 22 and 25 weeks’ gestation, found that a lower mortality rate associated with exposure to antenatal corticosteroids was partially offset by a higher rate of bronchopulmonary dysplasia among survivors compared to infants without exposure.3 A multicenter study of 2,549 infants less than 29 weeks’ gestation also found that the rate of bronchopulmonary dysplasia was higher in infants exposed to a complete course of antenatal corticosteroids compared to infants without exposure.4 Another multicenter study of 11,607 infants born 22 to 33 weeks’ gestation found that the rates of bronchopulmonary dysplasia did not differ in infants exposed to any antenatal corticosteroids compared to infants without exposure.5 These differences in bronchopulmonary dysplasia rates may be related to the different definition of bronchopulmonary dysplasia9 used in these studies as well as the gestational age inclusion criteria as inclusion of infants at the lowest gestations would result in more survivors who can develop bronchopulmonary dysplasia.
An important focus of the current study was the differential benefits of a partial or a complete course of antenatal corticosteroids. Although a complete course of antenatal corticosteroids is associated with a lower mortality compared to a partial course, the current study indicates that the first dose of antenatal corticosteroids may have the largest effect on reducing mortality. The Cochrane review of randomized controlled trials subgroup analysis of infants delivered following a partial course of antenatal corticosteroids showed a significant reduction in neonatal death in infants exposed to a partial course [four studies, 295 infants].1 The current study results are in concordance with those of an observational study of 9,949 infants weighing 501 to 1500 grams from the era before widespread use of antenatal corticosteroids and surfactant which found a lower rate of death before discharge in infants exposed to a partial course of antenatal corticosteroids compared to infants without exposure.6 In that study the rate of bronchopulmonary dysplasia also did not differ by degree of exposure to antenatal corticosteroids. The aforementioned study by Wong et al indicated that mortality did not differ in infants exposed to a partial course of antenatal corticosteroids compared to infants without exposure but this study was limited by a relatively small sample size.4
Strengths & Weaknesses
This study used data collected from top academic centers across the United States where optimal obstetric and neonatal care might be anticipated but there are several limitations which should be noted. There was no inception cohort of fetuses exposed or not exposed to antenatal corticosteroids. Data were not available on the exact timing of antenatal corticosteroids, whether fetal monitoring was undertaken prior to delivery, or the length of maternal hospitalization before delivery.23 There is a risk of bias as women admitted in advanced labor most likely would be overrepresented in the group that did not receive antenatal corticosteroids. While it is also unlikely that the results of this study are only due to confounding, there may be some residual unmeasured bias in the results due to baseline differences between the study groups which may not be adequately adjusted for in the models used. In addition, there is a possibility of postnatal bias in which infants not exposed to antenatal corticosteroids may have had their care restricted or withheld, particularly among infants at the lowest gestations. To reduce this effect, infants who died within 12 hours of birth without receiving delivery room resuscitation were excluded from the primary analysis. The multiple testing used in this study at a 5% significance level may have resulted in a few results being significant purely by chance. However, the benefits were consistent at most gestations, suggesting that the results are not only due to chance.
Research implications
Although antenatal corticosteroid administration reduces preterm infant mortality and morbidity without increasing the cost of care,1 many eligible women24 do not receive this treatment.11,12 Center differences in the use of antenatal corticosteroids are associated with mortality among infants at the lowest gestations.25,26 Differences between administration rates among infants by gestation in this study indicate that although administration rates are increasing, there are opportunities for quality improvement.26
Conclusion
The current study demonstrates that antenatal exposure to corticosteroids for infants 22 0/7 to 28 6/7 weeks’ gestation is associated with a lower rate of death before discharge without a higher rate of bronchopulmonary dysplasia or other major adverse pulmonary problems. This study also indicates that antenatal corticosteroids ameliorate the severity of respiratory distress syndrome and other important morbidities in extremely preterm infants.
Supplementary Material
Condensation.
Exposure to antenatal corticosteroids is associated with a lower rate of death which is not offset by a higher rate of bronchopulmonary dysplasia.
Acknowledgments
The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network’s Generic Database and Follow-up Studies through cooperative agreements. While NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Mr. Scott A. McDonald (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chairs: Alan H. Jobe, MD PhD, University of Cincinnati (2003–2006); Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–2011); Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011-present).
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – William Oh, MD; Martin Keszler, MD; Betty R. Vohr, MD; Robert T. Burke, MD MPH; Bonnie E. Stephens, MD; Yvette Yatchmink, MD; Barbara Alksninis, RNC PNP; Angelita M. Hensman, MS RNC-NIC; ; Kristin Basso, RN MaT; Elisa Vieira, RN BSN; Lenore Keszler, MD; Teresa M. Leach, MEd CAES; Martha R. Leonard, BA BS; Lucy Noel; Rachel A. Vogt, MD; Victoria E. Watson, MS CAS.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80) – Avroy A. Fanaroff, MD; Deanne E. Wilson-Costello, MD; Bonnie S. Siner, RN; Harriet G. Friedman, MA.
Children’s Mercy Hospital, University of Missouri Kansas City School of Medicine (U10 HD68284) – William E. Truog, MD; Eugenia K. Pallotto, MD MSCE; Howard W. Kilbride MD; Cheri Gauldin, RN BS CCRC; Anne Holmes, RN MSN MBA-HCM CCRC; Kathy Johnson, RN CCRC; Allison Knutson, RN BSN.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084) – Kurt Schibler, MD; Edward F. Donovan, MD; Kate Bridges, MD; Jean J. Steichen, MD; Kimberly Yolton, PhD; Barbara Alexander, RN; Estelle E. Fischer, MHSA MBA; Cathy Grisby, BSN CCRC; Marcia Worley Mersmann, RN; Holly L. Mincey, RN BSN; Jody Hessling, RN; Teresa L. Gratton, PA; Lenora D. Jackson, CRC; Kristin Kirker, CRC; Greg Muthig, BS.
Duke University School of Medicine, University Hospital, Duke Regional Hospital, and the University of North Carolina (U10 HD40492, M01 RR30) – C. Michael Cotten, MD MHS; Ricki F. Goldstein, MD; Kathy J. Auten, MSHS; Joanne Finkle, RN JD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Katherine A. Foy, RN; Sandra Grimes, RN BSN; Kathryn E. Gustafson, PhD; Melody B. Lohmeyer, RN MSN; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN; Cynthia L. Clark, RN.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39) – David P. Carlton, MD; Ira Adams-Chapman, MD; Yvonne C. Loggins, RN BSN; Diane I. Bottcher, RN MSN; Maureen Mulligan LaRossa, RN; Sheena L. Carter, PhD.
Eunice Kennedy Shriver National Institute of Child Health and Human Development–Linda L. Wright, MD; Elizabeth M. McClure, MEd; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750) – Gregory M. Sokol, MD; Brenda B. Poindexter, MD MS; James A. Lemons, MD; Anna M. Dusick, MD; Carolyn Lytle, MD MPH; Lon G. Bohnke, MS; Greg Eaken, PhD; Faithe Hamer, BS; Dianne E. Herron, RN; Abbey Hines, PsyD; Lucy C. Miller, RN BSN CCRC; Heike M. Minnich, PsyD HSPP; Lu-Ann Papile, MD; Leslie Richard, RN; Leslie Dawn Wilson, BSN CCRC.
Nationwide Children’s Hospital and The Ohio State University Wexner Medical Center (U10 HD68278) – Pablo J. Sánchez, MD; Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; Christine A. Fortney, RN, PhD; Keith Yeates, Ph.D; Melanie Stein, BBA, RRT; Julie Gutentag, RN, BSN; Tiffany Sharp, CMDA; Courtney Cira, RRT; Lina Yossef-Salameh, MD; Pamela Morehead, BS; Cody Brennan; Rox AnnSullivan, RN, BSN; Erin Fearns; Aubry Folwer; Jennifer Notestine, RN; Cole Hague, BA, MS; Jennifer L. Grothause, RN; Bronte Clifford, BA; Amanda Daubenmire Morely, BS; Erin Wishloff, RRT; Sarah Keim, BA, MA, MS, PhD; Helen Carey, DHSC; Christopher Timan, MD
RTI International (U10 HD36790) – W. Kenneth Poole, PhD (deceased); Dennis Wallace, PhD; Jamie E. Newman, PhD MPH; Jeanette O’Donnell Auman, BS; Margaret M. Crawford, BS CCRP; Betty K. Hastings; Elizabeth M. McClure, MEd; Carolyn M. Petrie Huitema, MS CCRP; Kristin M. Zaterka-Baxter, RN BSN CCRP. We thank Lei Li, PhD for his assistance with multiple imputation analyses. Stanford University, California Pacific Medical Center, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70) – Krisa P. Van Meurs, MD;
David K. Stevenson, MD; Susan R. Hintz, MD MS Epi; Marian M. Adams, MD; Charles E. Ahlfors, MD; Joan M. Baran, PhD; Barbara Bentley, PhD; Lori E. Bond, PhD; Ginger K. Brudos, PhD; Alexis S. Davis, MD MS; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN PNP; Barry E. Fleisher, MD; Lynne C. Huffman, MD; Jean G. Kohn, MD MPH; Casey Krueger, PhD; Julie C. Lee-Ancajas, PhD; Andrew W. Palmquist, RN; Melinda S. Proud, RCP; Renee P. Pyle, PhD; Dharshi Sivakumar, MD; Robert D. Stebbins, MD; Nicholas H. St. John, PhD; Halie E. Weiss, MD.
Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54) – Ivan D. Frantz III, MD; Elisabeth C. McGowan, MD; Brenda L. MacKinnon, RNC; Ellen Nylen, RN BSN; Anne Furey, MPH; Ana Brussa, MS OTR/L; Cecelia Sibley, PT MHA.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32) – Myriam Peralta-Carcelen, MD MPH; Kathleen G. Nelson, MD; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Stephanie A. Chopko, PhD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Mary Beth Moses, PT MS PCS; Vivien A. Phillips, RN BSN; Julie Preskitt, MSOT MPH; Richard V. Rector, PhD; Sally Whitley, MA OTR-L FAOTA.
University of California – Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270) – Uday Devaskar, MD; Meena Garg, MD; Isabell B. Purdy, PhD CPNP; Teresa Chanlaw, MPH; Rachel Geller, RN BSN.
University of California – San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461) – Neil N. Finer, MD; Maynard R. Rasmussen MD; Yvonne E. Vaucher, MD MPH; Paul R. Wozniak, MD; Kathy Arnell, RNC; Renee Bridge, RN; Clarence Demetrio, RN; Martha G. Fuller, RN MSN; Wade Rich, BSHS RRT.
University of Iowa and Mercy Medical Center (U10 HD53109, M01 RR59) – John A. Widness, MD; Dan L. Ellsbury, MD; Tarah T. Colaizy, MD MPH; Michael J. Acarregui, MD; Jane E. Brumbaugh, MD; Karen J. Johnson, RN BSN; Donia B. Campbell, RNC-NIC; Diane L. Eastman, RN CPNP MA.
University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587) – Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett-Thomas, RN MSN; Amy Mur Worth, RN MS; Mary Allison, RN; Alexis N. Diaz, BA; Elaine E. Mathews, RN; Kasey Hamlin-Smith, PhD; Lissa Jean-Gilles, BA; Maria Calejo, MS; Silvia M. Frade Eguaras, BA; Silvia Fajardo-Hiriart, MD; Yamiley C. Gideon, BA; Michelle Harwood Berkovits, PhD; Alexandra Stoerger, BA; Andrea Garcia, MA; Helena Pierre, BA; Georgette Roder, BSW; Arielle Riguad, MD.
University of New Mexico Health Sciences Center (U10 HD27881, U10 HD53089, M01 RR997) – Kristi L. Watterberg, MD; Andrea Freeman Duncan, MD MScr; Janell Fuller, MD; Robin K. Ohls, MD; Lu-Ann Papile, MD; Conra Backstrom Lacy, RN; Sandra Brown, RN BSN; Jean R. Lowe, PhD; Rebecca Montman, BSN.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (U10 HD68244) – Haresh Kirpalani, MB MSc; Sara B. DeMauro, MD MSCE; Aasma S. Chaudhary, BS RRT; Soraya Abbasi, MD; Toni Mancini, RN BSN CCRC; Dara M. Cucinotta, RN; Judy C. Bernbaum, MD; Marsha Gerdes, PhD; Hallam Hurt, MD.
University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (U10 HD68263, U10 HD40521, M01 RR44, UL1 TR42) – Dale L. Phelps, MD; Ronnie Guillet, MD PhD; Satyan Lakshminrusimha, MD; Gary J. Myers, MD; Erica Burnell, RN; Stephanie Guilford, BS; Cassandra A. Horihan, MS; Diane Hust, MS RN CS; Rosemary L. Jensen; Julie Babish Johnson, MSW; Emily Kushner, MA; Deanna Maffett, RN; Joan Merzbach, LMSW; Linda J. Reubens, RN CCRC; Ann Marie Reynolds, MD; Mary Rowan, RN; Holly I.M. Wadkins; Ashley Williams, MS Ed; Karen Wynn, NNP RN; Kelly Yost, PhD; Lauren Zwetsch, RN MS PNP.
University of Tennessee Health Science Center (U10 HD21415) – Sheldon B. Korones, MD; Henrietta S. Bada, MD; Tina Hudson, RN BSN; Marilyn Williams, LCSW; Kimberly Yolton, PhD.
University of Texas Southwestern Medical Center, Parkland Health & Hospital System and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – Luc P. Brion, MD; Pablo J. Sánchez, MD; Abbot R. Laptook, MD; Charles R. Rosenfeld, MD; Walid A. Salhab, MD; R. Sue Broyles, MD; Roy J. Heyne, MD; Merle Ipson, MD; Sally S. Adams, MS RN CPNP; P. Jeannette Burchfield, RN BSN; Lijun Chen, PhD RN; Cristin Dooley, PhD LSSP; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T. Heyne, MS MA PA-C PsyD; Jackie F. Hickman, RN; Melissa H. Leps, RN; Linda A. Madden, BSN RN CPNP; Susie Madison, RN; Nancy A. Miller, RN; Janet S. Morgan, RN; Lizette E. Torres, RN; Cathy Twell Boatman, MS CIMI; Diana M. Vasil, RNC-NIC.
University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373) – Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Patrick M. Jones, MD;
Patricia W. Evans, MD; Esther G. Akpa, RN BSN; Nora I. Alaniz, BS; Julie Arldt-McAlister, RN BSN; Katrina Burson, RN BSN; Magda Cedillo Guajardo, RB BSN FAACM; Susan E. Dieterich, PhD; Beverly Foley Harris, RN BSN; Claudia I. Franco, RNC MSN; Carmen Garcia, RN CCRP; Charles Green, PhD; Margarita Jiminez, MD MPH; Janice John, CPNP; Anna E. Lis, RN BSN; Terri Major-Kincade, MD MPH; Karen Martin, RN; Sara C. Martin, RN BSN; Georgia E. McDavid, RN; Brenda H. Morris, MD; Patricia Ann Orekoya, RN BSN; Patti L. Pierce Tate, RCP; M. Layne Poundstone, RN BSN; Stacey Reddoch, BA; Shawna Rodgers, RN; Saba Khan Siddiki, MD; Maegan C. Simmons, RN; Daniel Sperry, RN; Laura L. Whitely, MD; Sharon L. Wright, MT.
University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64) – Roger G. Faix, MD; Bradley A. Yoder, MD; Michael Steffen, MS CPM; Shawna Baker, RN; Karie Bird, RN; Jill Burnett, RN; Jennifer J. Jensen, RN BSN; Karen A. Osborne, RN BSN CCRC; Cynthia Spencer, RNC; Kimberlee Weaver-Lewis, RN MS; Sarah Winter, MD; Karen Zanetti, RN.
Wake Forest University Baptist Medical Center, Brenner Children’s Hospital, and Forsyth Medical Center (U10 HD40498, M01 RR7122) – T. Michael O’Shea, MD MPH; Robert G. Dillard, MD; Nancy J. Peters, RN CCRP; Korinne Chiu, MA; Deborah Evans Allred, MA LPA; Donald J. Goldstein, PhD; Raquel Halfond, MA; Barbara G. Jackson, RN BSN; Carroll Peterson, MA; Dia Roberts, BSN PNP; Ellen L. Waldrep, MS; Melissa Whalen Morris, MA; Gail Wiley Hounshell, PhD; Lisa K. Washburn, MD; Cherrie D. Welch, MD MPH.
Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385) – Beena G. Sood, MD MS; Athina Pappas, MD; John Barks, MD; Yvette R. Johnson, MD MPH; Rebecca Bara, RN BSN; Laura Goldston, MA; Mary E. Johnson, RN BSN; Deborah Kennedy, RN BSN; Geraldine Muran, RN BSN; Elizabeth Billian, RN MBA; Laura Sumner, RN BSN; Kara Sawaya, RN BSN; Mary K. Christensen, BA RRT; Stephanie A. Wiggins, MS.
Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 TR142, M01 RR125, M01 RR6022) – Richard A. Ehrenkranz, MD; Christine Butler, MD; Harris Jacobs, MD; Patricia Cervone, RN; Nancy Close, PhD; Patricia Gettner, RN; Walter Gilliam, PhD; Sheila Greisman, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Elaine Romano, MSN; Janet Taft, RN BSN; Joanne Williams, RN BSN.
Funding
National Institutes of Health. CP Travers is supported by Agency for Healthcare Research and Quality grant 5T32HS013852-14. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Agency for Healthcare Research and Quality. The funders had no role in: the study design; the collection, analysis, or interpretation of data; the writing of the report; or in the decision to submit the article for publication.
Footnotes
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Disclosure
The authors report; WA Carlo is on the board of MEDNAX, Inc; no other relationships or activities that could appear to have influenced the submitted work.
Registration
ClincalTrials.gov identifiers: NCT00063063 (Generic Database) and NCT00009633 (Follow-Up Study)
Paper Presentation Information
The findings in this paper were presented at Pediatric Academic Societies Annual Meeting, San Diego, California, April 25th to 28th, 2015.
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