Abstract
Objective
Test the hypothesis potential missed opportunities for antenatal corticosteroids increase as gestational age decreases and are associated with adverse outcomes.
Design
Observational cohort study.
Setting
24 US centers in the Neonatal Research Network.
Population
Actively treated infants 22–25 weeks’ gestation and birth weight 401–1000 grams, without major birth defects, born 2006–2018.
Methods
Potential missed opportunity was defined as no antenatal corticosteroids but did have prenatal antibiotics, and/or magnesium sulfate, and/or prolonged rupture of membranes. Poisson regression models adjusted for baseline characteristics.
Main Outcome Measures:
Antenatal corticosteroid exposure, mortality, and severe intracranial hemorrhage or periventricular leukomalacia.
Results
6966 (87.5%) were exposed to antenatal corticosteroids, 454 (5.7%) had no exposure but potential missed opportunities for antenatal corticosteroid exposure, and 537 (6.7%) had no exposure and no evidence of potential missed opportunities. Compared with infants born at 25 weeks, potential missed opportunities for antenatal corticosteroid exposure were more likely at 22 weeks (adjusted relative risk (aRR) [95% CI] 11.06 [7.52–16.27]) and 23 weeks (3.24 [2.44–4.29]) but did not differ at 24 weeks (1.08 [0.82–1.42]). Potential missed opportunities for antenatal corticosteroids decreased over time at 22–23 weeks’ gestation. Antenatal corticosteroid exposed infants had lower risk of death (31.0% vs 54.8%; 0.77 [0.70–0.84]) and survivors had lower risk of severe brain injury (25.0% v 44.5%; 0.64 [0.55–0.73]) compared with infants with potential missed opportunities.
Conclusion
Potential missed opportunities for antenatal corticosteroid exposure increased with decreasing gestational age and were associated with higher rates of death and severe brain injury among actively treated periviable births.
Keywords: Antenatal, prenatal, steroids, corticosteroids, steroids, periviable, extremely preterm, infant, newborn, births, potential, missed, opportunities, intracranial hemorrhage, intraventricular hemorrhage, mortality
Tweetable Abstract
Missed opportunities for antenatal steroids among periviable births are associated with death and brain injury
Introduction
Antenatal corticosteroid exposure reduces preterm infant mortality and major morbidities including intracranial hemorrhage.1 Observational studies suggest that the absolute benefit of antenatal corticosteroids may be highest among periviable infants.2,3 However, many eligible women4 do not receive this treatment5,6 and it is not known whether this is due to policy or a lack of opportunity. Consensus statements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine recommend to administer antenatal corticosteroids at 24 weeks’ gestation and recommend considering steroids at 23 weeks’ gestation, but until recently none of these groups have recommended administration at 22 weeks’ gestation4,7 even when active postnatal treatment is planned.8
It has previously been shown that periviable infants are more likely to be exposed to antibiotics before delivery than to antenatal corticosteroids.9 Treatment with intravenous medications, such as antibiotics or magnesium sulfate, or prolonged rupture of membranes before delivery may indicate that there was potentially sufficient time for intramuscular antenatal corticosteroid administration. We hypothesized that the rate of potential missed opportunities for antenatal corticosteroid exposure would increase as gestational age decreases among actively treated periviable infants. We further hypothesized that missed opportunities for antenatal corticosteroids would be associated with a higher rate of hospital mortality and/or severe brain injury.
Methods
Study population
This retrospective cohort study included infants without major birth defects born at 24 NICHD Neonatal Research Network centers between January 1, 2006 and December 31, 2018 with a gestational age of 22 0/7 to 25 6/7 weeks and a birth weight of 401 to 1000 grams. Best obstetrical estimate was used to determine gestational age if available; otherwise, we used best neonatal estimate.10 These infants were included in a registry of extremely preterm infants maintained by the Neonatal Research Network. The institutional review board at each center approved participation with either parental consent required or a waiver of consent allowed. Data were collected prospectively including maternal demographic, pregnancy and delivery information, and infant outcomes from birth to discharge, transfer, death, or 120 days. Beyond 120 days, limited outcome data were collected until discharge or death up to 1 year after birth. We followed the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.11 This study was funded by the National Institute of Child Health and Human Development (Grant number UG1 HD034216) and National Heart Lung and Blood Institute (Grant number K23HL157618). The funder was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Definitions
Antenatal corticosteroid exposure included infants exposed to partial, complete, or repeat courses of antenatal corticosteroids.1,12 Potential missed opportunities for antenatal corticosteroid exposure were defined as having no exposure to antenatal corticosteroids but having one or more of the following indicators that there was potentially sufficient time for intramuscular antenatal corticosteroid administration: receipt of antibiotics within 72 hours before delivery, administration of antenatal magnesium sulfate (collected beginning April 2011), and/or rupture of membranes more than 18 hours before delivery. Small for gestational age (SGA) was defined as birth weight < 10th percentile for sex and gestational age.13 Severe brain injury was defined as severe intracranial hemorrhage or periventricular leukomalacia on cranial imaging. Severe intracranial hemorrhage (ICH) was defined as ventricular enlargement with concurrent or prior blood in the ventricles or parenchyma blood or echodensity.14 Periventricular leukomalacia (PVL) was defined as cysts or echolucencies in the periventricular white matter. Active postnatal treatment was defined as any of the following: intubation, surfactant, continuous positive airway pressure, bag-and-mask, mechanical ventilation, chest compressions, epinephrine, volume resuscitation, inotrope support, or parenteral nutrition.8,9,15
Exposure and outcomes
The primary outcome was the overall rate of antenatal corticosteroid exposure and potential missed opportunities for exposure at each gestational age. Secondary outcomes included death, severe ICH/PVL or death, severe ICH/PVL alone, and changes in rates of antenatal corticosteroid exposure and potential missed opportunities for exposure by gestational age over time. The composite outcome of severe ICH/PVL or death was defined in two different ways: (1) severe ICH/PVL or death before evaluation by cranial imaging, and (2) severe ICH/PVL or death before discharge.
Statistical analysis
Infants who received active postnatal treatment were included in the primary analysis. Infants were excluded from all analyses if missing data needed to define exposure groups or active treatment. The proportions of infants exposed to antenatal corticosteroids and with potential missed opportunities for exposure were examined overall, by gestational age, and by birth year. Graphs of the proportions by birth year included a local weighted regression (LOESS) curve with a smoothing parameter of 0.4 to fit a smooth curve over the scatter plots to aid in visualization of trends over time. Statistical significance for unadjusted comparisons between infants in the antenatal corticosteroids and potential missed opportunities for antenatal corticosteroids groups was determined by chi-square test for categorical variables and Kruskal-Wallis test for continuous variables.
Poisson regression models with robust variance estimators were used to assess adjusted comparisons between groups.16 Adjusted relative risks (aRR), 95% confidence intervals (CI), and p-values by the score or Wald chi-square test from these models are reported. All model covariates were selected a priori and comprised known risk factors for adverse outcomes including study center, maternal characteristics (age, race/ethnicity, education, medical insurance, marital status, any prenatal care, insulin-dependent diabetes, chronic or pregnancy-induced hypertensive disorders, antepartum hemorrhage, clinical chorioamnionitis, multiple birth, and delivery mode) and infant characteristics (sex, birth weight in grams, and gestational age in weeks). Maternal education was missing for 23% of the cohort and was entered in models with a level indicating missing in order to minimize exclusion of observations with missing values. Each of the other covariates were missing for <1% of infants. In total, 2.6% of observations were excluded from models due to missing covariates. The adjusted risk of potential missed opportunities for antenatal corticosteroids at each gestational age was compared with the risk for those born at 25 weeks. Temporal changes in rates of antenatal corticosteroid exposure and in potential missed opportunities were examined with a model that included birth year (continuous) and the interaction between birth year and gestational age in addition to the covariates above.
Secondary outcomes, including death and severe brain injury, were compared between infants in the antenatal corticosteroid and potential missed opportunities for antenatal corticosteroid groups using models that allowed for interaction between exposure group and gestational age, while controlling for the other factors listed above. The interaction was not significant for the outcomes studied, indicating no statistically significant difference in the exposure-outcome relationship by gestational age. Therefore, the overall aRRs from main effects models and associated p-values were reported. As a sensitivity analysis, associations between antenatal corticosteroid exposure and secondary outcomes were also examined after excluding the 46 women included in the potential missed antenatal corticosteroid group due to prolonged rupture alone. Further, to determine if associations between antenatal corticosteroid exposure and outcomes changed over time we conducted a sensitivity analysis examining three-year periods with the exception that the first period was 4 years: 2006–2009, 2010–2012, 2013–2015, 2016–2018. Models included the interaction between exposure group and birth year period. Sensitivity analyses to examine the proportion of infants with potential missed opportunities for antenatal corticosteroids exposure by gestational and to assess trends in antenatal corticosteroid exposure were conducted using data from all infants, including those not actively treated. Trends in exposure were also examined among actively treated infants in the subset of 11 centers that participated in the Neonatal Research Network during all study years. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). P-values less than 0.05 were considered statistically significant.
Results
Study population
The total cohort included 8967 infants after exclusion of 396 infants with congenital anomalies and 339 infants missing exposure variables (Figure S1). The primary analysis included 7957 (88.7%) infants who were actively treated postnatally. Of these, 6966 were exposed to antenatal corticosteroids (87.5%), 454 (5.7%) had no exposure to antenatal corticosteroids but potential missed opportunities for exposure, and 537 (6.7%) had no exposure and no apparent potential missed opportunities for exposure to antenatal corticosteroids. The mean (standard deviation) gestational age of infants actively treated was 24.1 (0.9) weeks with a birth weight of 672 (127) grams. The proportion of actively treated infants varied by gestational age (22 weeks: 32.1%, 23 weeks: 83.1%, 24 weeks: 98.2%, 25 weeks: 99.7%, p<0.001) and by exposure group (Table 1).
Table 1.
Proportion of infants actively treated at birth by gestational age and antenatal corticosteroid (ANS) group
| Any ANS n/N (column %) |
Potential missed ANS n/N (column %) |
No ANS exposure or potential n/N (column %) |
All n/N (column %) |
|
|---|---|---|---|---|
| By gestational age week | ||||
| 22 | ||||
| Active treatment | 170/214 (79.4) | 70/352 (19.9) | 48/332 (14.5) | 288/898 (32.1) |
| No active treatment | 44/214 (20.6) | 282/352 (80.1) | 284/332 (85.5) | 610/898 (67.9) |
| 23 | ||||
| Active treatment | 1,333/1,432 (93.1) | 158/296 (53.4) | 162/262 (61.8) | 1,653/1,990 (83.1) |
| No active treatment | 99/1,432 (6.9) | 138/296 (46.6) | 100/262 (38.2) | 337/1,990 (16.9) |
| 24 | ||||
| Active treatment | 2,573/2,608 (98.7) | 106/116 (91.4) | 147/155 (94.8) | 2,826/2,879 (98.2) |
| No active treatment | 35/2,608 (1.3) | 10/116 (8.6) | 8/155 (5.2) | 53/2,879 (1.8) |
| 25 | ||||
| Active treatment | 2,890/2,897 (99.8) | 120/122 (98.4) | 180/181 (99.4) | 3,190/3,200 (99.7) |
| No active treatment | 7/2,897 (0.2) | 2/122 (1.6) | 1/181 (0.6) | 10/3,200 (0.3) |
| All gestational ages | ||||
| Active treatment | 6,966/7,151 (97.4) | 454/886 (51.2) | 537/930 (57.7) | 7,957/8,967 (88.7) |
| No active treatment | 185/7,151 (2.6) | 432/886 (48.8) | 393/930 (42.3) | 1,010/8,967 (11.3) |
Actively treated infants exposed to antenatal corticosteroids were more likely to have mothers with more than a high school degree, private medical insurance, and with at least one prenatal visit than actively treated infants with potential missed opportunities for exposure (Table 2). The proportion of White non-Hispanic mothers was higher in the antenatal corticosteroid group while the proportion of Hispanic mothers was lower. Breech vaginal delivery occurred more often in the potential missed opportunities group while cesarean delivery was more frequent in the antenatal corticosteroid exposed group.
Table 2.
Baseline maternal and infant characteristics among infants actively treated at birth and antenatal corticosteroid (ANS) expsoure
| n (column %) or as shown* | Any ANS N=6966 |
Potential Missed ANS N=454 |
P-value† |
|---|---|---|---|
| Study criteria for groups | |||
| Maternal antibiotics <72 hours prior to birth | 5551 (79.7) | 365 (80.4) | 0.72 |
| Antenatal magnesium sulfate‡ | 3637/4310 (84.4) | 116/262 (44.3) | <0.001 |
| Rupture of membranes >18 hours before delivery | 2100 (30.1) | 136 (30.0) | 0.93 |
| Maternal and delivery characteristics | |||
| Maternal age in y, mean (SD) | 27.9 (6.3) | 27.4 (6.4) | 0.18 |
| Married | 3138 (45.4) | 181 (40.6) | 0.05 |
| Highest level of education | <0.001 | ||
| < High School | 1036/5382 (19.2) | 109/337 (32.3) | |
| High School degree | 1648/5382 (30.6) | 115/337 (34.1) | |
| > High School | 2698/5382 (50.1) | 113/337 (33.5) | |
| Mother’s medical insurance | <0.001 | ||
| Public | 3705 (53.5) | 276 (61.9) | |
| Private | 2814 (40.7) | 114 (25.6) | |
| Self-pay/uninsured/other | 401 (5.8) | 56 (12.6) | |
| Mother’s race/ethnicity§ | <0.001 | ||
| Black non-Hispanic | 2830 (40.8) | 189 (41.9) | |
| White non-Hispanic | 2742 (39.5) | 132 (29.3) | |
| Hispanic | 1012 (14.6) | 109 (24.2) | |
| Other | 349 (5.0) | 21 (4.7) | |
| At least 1 prenatal visit | 6684 (96.1) | 416 (91.8) | <0.001 |
| Insulin dependent diabetes | 284 (4.1) | 30 (6.7) | 0.01 |
| Maternal hypertension | 1408 (20.2) | 101 (22.2) | 0.30 |
| Antepartum hemorrhage | 1505 (21.6) | 113 (24.9) | 0.10 |
| Chorioamnionitis | 1436 (20.6) | 104 (23.0) | 0.24 |
| Multiple birth | 1824 (26.2) | 114 (25.1) | 0.61 |
| Delivery mode | <0.001 | ||
| Vaginal vertex | 2319 (33.3) | 169 (37.4) | |
| Vaginal breech | 476 (6.8) | 71 (15.7) | |
| Cesarean section | 4167 (59.9) | 212 (46.9) | |
| Infant characteristics | |||
| Gestational age in weeks, mean (SD) | 24.2 (0.8) | 23.6 (1.0) | <0.001 |
| By gestational age week | <0.001 | ||
| 22 | 170 (2.4) | 70 (15.4) | |
| 23 | 1333 (19.1) | 158 (34.8) | |
| 24 | 2573 (36.9) | 106 (23.3) | |
| 25 | 2890 (41.5) | 120 (26.4) | |
| Birth weight in grams, mean (SD) | 674 (126) | 641 (128) | <0.001 |
| Small for gestational age | 450 (6.5) | 14 (3.1) | 0.004 |
| Male | 3592 (51.6) | 222 (48.9) | 0.27 |
Percent denominators are shown for characteristics not collected all years (magnesium sulfate) and for characteristics with information missing for >1% of infants (maternal education). Otherwise, information was missing for: marital status, 55 infants; maternal medical insurance, 54 infants; mother’s race/ethnicity, 36 infants; prenatal care, 11; insulin-dependent diabetes, 22; maternal hypertension, 3; antepartum hemorrhage, 7; chorioamnionitis, 8; delivery mode, 6; SGA, 4; male sex, 4.
P-value by chi-square test (categorical variables) or Kruskal-Wallis test (continuous variables).
Magnesium sulfate was collected beginning April 1, 2011.
Maternal ethnicity was classified as non-Hispanic for 4% of infants whose mothers reported race as Black and <1% of infants whose mothers reported race as White but for whom ethnicity was not reported. The 370 infants with other maternal race includes 74% Asian/pacific islander, 13% American Indian or Alaska native, and 13% more than one race.
The proportions of infants in the antenatal corticosteroids and potential missed opportunities groups with mothers who received antibiotics in the 72 hours before birth and had rupture of membranes more than 18 hours did not differ (Table 2). A larger proportion of infants exposed to antenatal corticosteroids also received magnesium sulfate (84.4% vs 44.3%, p<0.001). Ten percent of infants in the potential missed opportunities group were included in that group solely due to rupture of membranes more than 18 hours and the proportion did not differ by gestational age.
Antenatal corticosteroid exposure and potential missed opportunities
The proportions of actively treated infants exposed to antenatal corticosteroids and with potential missed opportunities for exposure varied by gestational age (Figure 1). Receipt of antenatal corticosteroids varied by gestational age (22 weeks: 59.0%, 23 weeks: 80.6%, 24 weeks: 91.0%, 25 weeks: 90.6%). Compared with infants born at 25 weeks, potential missed opportunities for exposure to antenatal corticosteroids were more common for infants born at 22 weeks (aRR [95% CI]: 11.06 [7.52–16.27], p<0.001) and 23 weeks (3.24 [2.44–4.29], p<0.001) after controlling for potential confounding factors. There was no difference in rates of potential missed opportunities for antenatal corticosteroids between infants born at 24 and 25 weeks.
Figure 1.
Proportion of actively treated infants with antenatal corticosteroid (ANS) exposure, potential missed opportunities for ANS exposure, and no ANS and no evidence of potential missed opportunities for ANS exposure at each gestational age. The proportion of infants exposed to antenatal corticosteroids increased with increasing gestational age at 22 and 23 weeks’ gestation and did not differ between infants at 24 and 25 weeks’ gestation. The proportion of infants with potential missed opportunities for exposure to antenatal corticosteroids decreased with increasing gestational age at 22 and 23 weeks’ gestation and did not differ between infants at 24 and 25 weeks’ gestation.
During the study period, antenatal corticosteroid exposure increased overall from 79.2% (471/595) in 2006 to 91.5% (582/636) in 2018 (p<0.001). Correspondingly, potential missed opportunities for antenatal corticosteroid exposure decreased from 7.9% (47/595) in 2006 to 4.7% (30/636) in 2018 (p=0.001) (Appendix 1). The increase in antenatal corticosteroid exposure varied by gestational age with the largest increase among actively treated infants born at 22 weeks, from 12.5% (2/16) in 2006 to 87.2% (34/39) in 2018, an increase of about 10% per year (aRR [95% CI] per year increase: 1.10 [1.07–1.14]) (Figure 2, Appendix 1). For infants born at 23 weeks, antenatal corticosteroid exposure increased from 59.8% (64/107) to 89.0% (138/155) during the study period while smaller increases were observed among infants born at 24 weeks and those born at 25 weeks. The rate of potential missed opportunities for exposure decreased among infants born at 22 weeks from 68.8% (11/16) in 2006 to 2.6% (1/39) in 2018, a decrease of about 10% per year (0.90 [0.85–0.95], p<0.001). The rate in infants born at 23 weeks also decreased from 16.8% (18/107) in 2006 to 3.9% (6/155) in 2018, p<0.001. The proportion of infants born at 24 and 25 weeks with potential missed opportunities for exposure to antenatal corticosteroids remained low throughout.
Figure 2.
Rates of antenatal corticosteroid (ANS) exposure and potential missed opportunities for ANS exposure 2006–2018 among infants actively treated at birth. Circles and crosses indicate the percent of infants born each year in the exposure groups, the smoothed lines show the trends, and the shading shows the 95% CI for the curves. The year by GA interaction was significant, p<0.001, for both rates.
Infant Outcomes
Overall, 66.4% (5269/7934) of actively treated infants survived to discharge. The proportion of infants who died before discharge was lower among infants exposed to antenatal corticosteroids than among those with potential missed opportunities for antenatal corticosteroids (Table 3). Mortality was 23% lower overall for infants exposed to antenatal corticosteroids than for those in the potential missed opportunities group (31.0% vs 54.8%, aRR [95% CI]: 0.77 [0.70–0.84], p<0.001, number needed to treat for benefit (NNTb) [95% CI]: 5 [4–6]). Death occurred within 12 hours of birth in 5.5% of infants exposed to antenatal corticosteroids compared with 22.7% of infants in the potential missed opportunities for antenatal corticosteroids group (aRR [95% CI]: 0.47 [0.37–0.59], p<0.001, NNTb [95% CI]: 6 [5–8]).
Table 3.
Outcomes by exposure to antenatal corticosteroids (ANS) among infants actively treated at birth
| Outcome* | Any ANS N=6966 |
Potential Missed ANS N=454 |
aRR (95% CI) † | P-value‡ |
|---|---|---|---|---|
| Death, n/N (%) | ||||
| All gestational ages | 2153/6943 (31.0) | 249/454 (54.8) | 0.77 (0.70–0.84) | <0.001 |
| 22 | 108/169 (63.9) | 57/70 (81.4) | 0.91 (0.77–1.08) | |
| 23 | 621/1333 (46.6) | 114/158 (72.2) | 0.73 (0.65–0.83) | |
| 24 | 830/2560 (32.4) | 48/106 (45.3) | 0.69 (0.56–0.86) | |
| 25 | 594/2881 (20.6) | 30/120 (25.0) | 0.81 (0.59–1.10) | |
| Death ≤12 h, n/N (%) | ||||
| All gestational ages | 386/6966 (5.5) | 10¾54 (22.7) | 0.47 (0.37–0.59) | <0.001 |
| 22 | 25/170 (14.7) | 30/70 (42.9) | 0.47 (0.30–0.73) | |
| 23 | 141/1333 (10.6) | 53/158 (33.5) | 0.47 (0.35–0.64) | |
| 24 | 147/2573 (5.7) | 12/106 (11.3) | 0.57 (0.32–1.01) | |
| 25 | 73/2890 (2.5) | 8/120 (6.7) | 0.35 (0.17–0.72) | |
| Severe ICH/PVL or death before evaluation, n/N (%) | ||||
| All gestational ages | 2179/6947 (31.4) | 274/452 (60.6) | 0.64 (0.59–0.71) | <0.001 |
| 22 | 86/170 (50.6) | 57/70 (81.4) | 0.66 (0.54–0.80) | |
| 23 | 580/1328 (43.7) | 115/157 (73.2) | 0.65 (0.57–0.74) | |
| 24 | 839/2568 (32.7) | 56/105 (53.3) | 0.63 (0.52–0.77) | |
| 25 | 674/2881 (23.4) | 46/120 (38.3) | 0.63 (0.50–0.80) | |
| Severe ICH/PVL or death before discharge, n/N (%) | ||||
| All gestational ages | 3104/6948 (44.7) | 316/453 (69.8) | 0.78 (0.73–0.84) | <0.001 |
| 22 | 124/170 (72.9) | 62/70 (88.6) | 0.89 (0.78–1.02) | |
| 23 | 817/1329 (61.5) | 139/158 (88.0) | 0.75 (0.69–0.82) | |
| 24 | 1198/2568 (46.7) | 63/105 (60.0) | 0.78 (0.66–0.92) | |
| 25 | 965/2881 (33.5) | 52/120 (43.3) | 0.77 (0.62–0.95) | |
| Survived >12 h and had cranial imaging, N | 6,371 | 323 | ||
| Severe ICH/PVL, n/N (%) | ||||
| All gestational ages | 1586/6354 (25.0) | 143/321 (44.5) | 0.64 (0.55–0.73) | <0.001 |
| 22 | 46/130 (35.4) | 21/34 (61.8) | 0.55 (0.38–0.79) | |
| 23 | 390/1138 (34.3) | 52/94 (55.3) | 0.64 (0.51–0.79) | |
| 24 | 605/2334 (25.9) | 39/88 (44.3) | 0.61 (0.48–0.79) | |
| 25 | 545/2752 (19.8) | 31/105 (29.5) | 0.72 (0.53–0.98) |
Information was missing for: final status, 23 infants; severe ICH/PVL or death before evaluation, 21; severe ICH/PVL or death before discharge, 19; severe ICH/PVL, 19. For both composite outcomes, 724 infants who died ≤12 hours after birth or died after 12 hours but before evaluation by cranial imaging, 1018 infants who had severe ICH/PVL and survived to discharge, and 711 infants who had severe ICH/PVL and later died were counted as having the outcome. For the second composite outcome an additional 967 infants without severe ICH/PVL on cranial imaging who died before discharge were counted as having the outcome.
Adjusted relative risks (aRR) and confidence intervals (CI) from models that included ANS group (any ANS, potential missed opportunities ANS), study center, mother’s age (continuous), mother’s race/ethnicity (non-Hispanic Black, non-Hispanic White, Hispanic, other), mother’s education (<high school degree, high school degree, >high school degree), mother’s medical insurance (public, private, self-pay/uninsured/other), marital status, at least one prenatal visit, insulin-dependent diabetes, maternal hypertension, antepartum hemorrhage, chorioamnionitis recorded in the mother’s medical record, multiple birth, delivery mode (vaginal vertex, vaginal breech, cesarean section), infant male sex, birth weight (continuous), and gestational age (22, 23, 24, 25 weeks). Initial models included the interaction between ANS group and gestational age. The interaction was not significant for any outcome (death before discharge: p=0.16; death within 12 hours: p=0.79; severe ICH/PVL or death before evaluation: p=0.99; severe ICH/PVL or death before discharge: p=0.19; severe ICH/PVL: p=0.72 by the score chi-square test). Thus, for each outcome the overall aRR and associated p-value is shown. Proportions and aRRs are shown by gestational age for descriptive purposes.
Statistical significance was determined by the Wald chi-square test.
Most actively treated infants who survived >12 hours had cranial imaging (7119/7381, 96%). Of these, 25.0% in the antenatal corticosteroid group and 44.5% in the potential missed antenatal corticosteroid group were diagnosed with severe ICH and/or PVL (aRR [95% CI]: 0.64 [0.55–0.73], p<0.001, NNTb [95% CI]: 6 [4–8]) with no significant variation in the relative differences by gestational age. Severe ICH/PVL or death before evaluation by cranial imaging occurred in 31.4% of infants exposed to antenatal corticosteroids compared with 60.6% who had potential missed opportunities for antenatal corticosteroids (aRR [95% CI]: 0.64 [0.59–0.71], p<0.001, NNTb [95% CI]: 4 [3–5]). Severe ICH/PVL or death before discharge occurred in 44.7% of infants exposed to antenatal corticosteroids compared with 69.8% in the potential missed opportunities for antenatal corticosteroids (aRR [95% CI]: 0.78 [0.73–0.84], p<0.001, NNTb [95% CI]: 4 [4–5]).
Sensitivity Analyses
In the complete cohort of 8967 infants, including those not actively treated, the proportions of infants in the antenatal corticosteroid and potential missed opportunities groups varied by gestational age (Appendix 2). Infants born at 22 and 23 weeks were at higher risk for being in the potential opportunities group than infants born at 25 weeks. There was no difference in rates of potential missed opportunities between infants born at 24 and 25 weeks. Antenatal corticosteroid exposure increased overall from 69.6% (495/711) of infants born in 2006 to 86.5% (594/687) of infants born in 2018 (p<0.001) and the largest increase was among infants born at 22 weeks, from 7.3% (6/82) in 2006 to 50.0% (39/78) in 2018 (Appendix 3). Potential missed opportunities for antenatal corticosteroid exposure decreased overall during the period from 12.9% (92/711) in 2006 to 7.4% (51/687) in 2018 (p=0.02) and the largest decrease was among infants born at 22 weeks from 48.8% (40/82) in 2006 to 24.4% (19/78) in 2018 (Appendix 3). The proportion of actively treated infants with potential missed opportunities for antenatal corticosteroids varied across centers at each gestational age (Appendix 4). Changes in rates of exposure and potential missed opportunities for antenatal corticosteroid exposure in the subset of 5327 actively treated infants from centers that participated during all study years were similar in magnitude to those reported for all centers (data not shown).
Among actively treated infants, the relationships between antenatal corticosteroid exposure and the outcomes studied did not vary significantly over the periods (antenatal corticosteroid group x birth year period interaction: death, p=0.30; death ≤12 hours, p=0.21; severe ICH/PVL or death before evaluation, p=0.36; severe ICH/PVL or death before discharge, p=0.41; and severe ICH/PVL in infants who had cranial imaging, p=0.69). In each period, adjusted risks for each outcome were lower for infants exposed to antenatal corticosteroids versus those not exposed. During the most recent years, 2016–2018, the adjusted relative risks [95% CI] for infants exposed versus not exposed to antenatal corticosteroids were: death, 0.66 [0.53–0.81]; death ≤12 hours, 0.32 [0.20–0.52]; severe ICH/PVL or death before evaluation, 0.59 [0.49–0.70]; severe ICH/PVL or death before discharge, 0.70 [0.60–0.82]; severe ICH/PVL in infants with cranial imaging, 0.58 [0.44–0.76]. A sensitivity analysis excluding the 46 women included in the potential missed antenatal corticosteroid group due to prolonged rupture alone differed minimally from the adjusted RRs reported in the primary analysis (data not shown).
Discussion
Main Findings
This study demonstrates that among infants born at 22–25 weeks who receive active postnatal treatment potential missed opportunities for antenatal corticosteroids are more common at the lowest gestational ages. Potential missed opportunities for antenatal corticosteroid exposure were observed for nearly one fourth of infants born at 22 weeks and one tenth of those born at 23 weeks. However, the proportion of infants actively treated who were exposed to antenatal corticosteroids increased during the years studied, especially for infants born at 22 and 23 weeks. Furthermore, antenatal corticosteroid exposure was associated with lower rates of mortality and severe brain injury. It is possible that increasing the rate of antenatal corticosteroid exposure may further improve outcomes among actively treated periviable infants.
Strengths and Limitations
We did not have data available on timing of maternal admission. Therefore, we used surrogates, including maternal antibiotics prior to delivery, magnesium sulfate, and prolonged rupture of membranes, to evaluate potential missed opportunities for antenatal corticosteroids. The use of these surrogate measures is supported by the decreases in potential missed opportunities with corresponding increases in antenatal corticosteroid exposure. Thus, the changes in antenatal corticosteroid exposure and potential missed opportunities among infants at the lowest gestations in the current study likely reflect changes in perinatal decision-making over time. Furthermore, the low rate and lack of difference in potential missed opportunities at 24 to 25 weeks’ gestation supports our hypothesis. While all infants included in our primary analysis were actively treated, it is possible that some decisions to provide neonatal resuscitation were made postnatally or that postnatal bias related to receipt of antenatal corticosteroids may have affected later treatment decisions.
Our study did not include an inception cohort of mothers who presented with threatened preterm birth but rather analyzed data based on gestational age at birth. Therefore, we do not have data on outcomes of infants whose mothers presented with threatened preterm birth but who then delivered at later gestations. However, meta-analyses of randomized clinical trials of antenatal corticosteroid exposure demonstrated no difference in pregnancy length after corticosteroid exposure and also reported that antenatal corticosteroids improved survival and decreased intraventricular hemorrhage among preterm infants when analyzed by gestational age at delivery as well as by gestational age at trial entry. Antenatal corticosteroids are recommended when preterm delivery is thought to be imminent and have no direct effect on age at delivery. Our data, and data from the meta-analysis of randomized clinical trials of antenatal corticosteroid exposure, suggest that gestational age at birth is not a collider or mediator variable but is a confounder for which adjustment is appropriate.17
We used data from a subset of academic medical centers but US population-based datasets do not collect such detailed information on perinatal care practices and outcomes.18 Population-based studies in other high-income countries have found an association between antenatal corticosteroids and improved outcomes.19,20 Many infants exposed to antenatal corticosteroids at periviable gestations deliver beyond the periviable period6 but data on infants exposed but delivered later were not available. This study did not evaluate other major outcomes following preterm birth including neurodevelopmental impairment, bronchopulmonary dysplasia, respiratory distress syndrome, or necrotizing enterocolitis that have been associated with antenatal corticosteroid exposure.
Interpretation
The mother is recognized as the autonomous decision maker with regard to treatments that may affect her and her fetus.21,22 As such, consensus statements recommend that infants who are considered potentially viable based on clinical circumstances and family desires should be treated in a manner consistent with pregnancies at higher gestations.4 In the current study, rates of antenatal corticosteroid use increased among periviable infants. This may reflect assimilation of newer data on the association between antenatal corticosteroids exposure with higher rates of survival and lower rates of major morbidities among infants at the lowest gestations.2,3,23,24 While discordance between obstetric and neonatal management at the limits of viability has been noted,9 increasing rates of antenatal corticosteroid administration among periviable infants suggest that discordance may be decreasing over time in Neonatal Research Network centers.
Until recently, professional guidelines from the American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine did not recommend antenatal corticosteroid administration at 22 weeks’ gestation.7 This recommendation was classified as Grade 1A evidence consistent with evidence from well-conducted randomized controlled trials or other overwhelming evidence of benefit or harm.25 Randomized clinical trials of antenatal corticosteroids were conducted during years when infants at 22 to 23 weeks’ gestation were generally considered below the limit of viability26 and included relatively few infants less than 26 weeks’ gestation. Further randomized controlled trials among periviable infants are unlikely given the benefits at higher gestations.1 Findings of our study are consistent with observational studies that suggest the absolute benefit of antenatal corticosteroids may be highest among periviable infants.2,3
It is not known how the desire to achieve optimal timing of antenatal corticosteroids factored into perinatal decision-making in this study. Our definition of antenatal corticosteroids exposure included partial, complete, or repeat courses. Partial courses of antenatal corticosteroids decreased mortality among preterm infants in the meta-analysis of randomized controlled trials and observational studies that included periviable infants.1,24 While antenatal corticosteroid administration 24–47 hours before delivery is associated with the lowest risk of death27 even administration within 3 hours of delivery may lower the risk of death28. As the effect on mortality may begin to wane after 1–2 weeks it is possible that some infants in the current study, particularly at higher gestational ages, may have been exposed to repeat courses. However, repeat courses have not been demonstrated to decrease mortality or severe brain injury.29
We noted baseline differences between groups in the current study including maternal race/ethnicity, insurance status, education level, and prenatal care. While our models were adjusted for these factors, it is known that rates of active postnatal treatment vary by race/ethnicity and socioeconomic status.8,30 The differences we observed in receipt of antenatal corticosteroids by race/ethnicity are consistent with data from observational studies.31,32 Lack of prenatal care has been associated with lower rates of exposure to antenatal corticosteroids2 emphasizing the importance of prenatal care.
Conclusions
Potential missed opportunities for antenatal corticosteroid exposure increased with decreasing gestational age among actively treated periviable infants. During the study period the rate of potential missed opportunities decreased while the rate of antenatal corticosteroid administration increased especially for infants born at 22 or 23 weeks. Exposure to antenatal corticosteroids was associated with lower rates of death and severe brain injury in the event of delivery before 26 weeks’ gestation.
Supplementary Material
Acknowledgements
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 Study 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, RTI International had full access to all of the data in the study, and with the NRN Center Principal Investigators, takes 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 Chair: Chair: Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011-present); Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine.
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Abbott R. Laptook, MD; Martin Keszler, MD; Angelita M. Hensman, PhD RNC-NIC; Andrea M. Knoll; Emilee Little, RN BSN; Elisa Vieira, RN BSN; Kristin M. Basso, RN MaT; Jennifer A. Keller, RN BSN; Lucille St. Pierre, BS.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80) – Michele C. Walsh, MD MS; Anna Maria Hibbs, MD; Avroy A. Fanaroff, MD; Nancy S. Newman, BA RN; Allison H. Payne, MD MS.
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, BSN RNC-NIC; Prabhu S. Parimi, MD; Lisa Gaetano, RN MSN.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084) – Stephanie L. Merhar, MD MS; Brenda B. Poindexter, MD MS; Kurt Schibler, MD; Edward F. Donovan, MD; Cathy Grisby, BSN CCRC; Barbara Alexander, RN; Kate Bridges, MD; Estelle E. Fischer, MHSA MBA; Holly L. Mincey, RN BSN; Jody Hessling, RN; Lenora Jackson, CRC; Kristin Kirker, CRC; Greg Muthig, BS; Stacey Tepe, BS.
Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, UL1 TR1117, M01 RR30, UL1 TR1111) – C. Michael Cotten, MD MHS; Ronald N. Goldberg, MD; Joanne Finkle, RN JD; Kathy J. Auten, MSHS; Kimberley A. Fisher, PhD FNP-BC IBCLC; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN; Cindy Clark, RN; Stephen D. Kicklighter, MD; Ginger Rhodes-Ryan, ARNP MSN NNP-BC; Donna White, BSN RN-BC.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39) – Ravi M. Patel, MD; David P. Carlton, MD; Barbara J. Stoll, MD; Ellen C. Hale, RN BS CCRC; Yvonne Loggins, RN BSN; Diane I. Bottcher, RN MSN; Colleen Mackie, BS RT.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Andrew A. Bremer, MD PhD; Rosemary D. Higgins, MD; 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; Dianne E. Herron, RN CCRC; Jeff Joyce, CCRC; Lucy Miller, BSN CCRC; Leslie Dawn Wilson, BSN CCRC.
McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, Memorial Hermann Southwest Hospital and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373) –Jon E. Tyson, MD MPH; Amir M. Khan, MD; Kathleen A. Kennedy, MD MPH; Elizabeth Eason, MD; Emily K. Stephens, BSN RNC-NIC; Georgia E. McDavid, RN; Julie Arldt-McAlister, RN BSN; Katrina Burson, RN BSN; Carmen Garcia, RN CCRP; Donna Hall, RN; Beverly Foley Harris, RN BSN; Anna E. Lis, RN BSN; Karen Martin, RN; Sara C. Martin, RN BSN; Shawna Rodgers, RN; Maegan C. Simmons, RN; Barbara J. Stoll, MD; Patti L. Pierce Tate, RCP.
Nationwide Children’s Hospital, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Center for Perinatal Research, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Riverside Methodist Hospital (U10 HD68278) – Pablo J. Sanchez, MD; Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; Hallie Baugher, BS MSN; Erna Clark, BA; Christine A. Fortney, PhD RN; Julie Gutentag, RN; Courtney Park, RN; Julie C. Shadd, BSN RD; Melanie Stein, RRT BBA; Jennifer L. Grothause, RN BSN; Jacqueline McCool; Nehal A. Parikh, MD; Lina Yosseff-Salameh, MD.
RTI International (U10 HD36790) –Marie G. Gantz, PhD; Carla M. Bann, PhD; Dennis Wallace, PhD; Margaret M. Crawford, BS CCRP; Jenna Gabrio, MPH CCRP; David Leblond, BS; Jeanette O’Donnell Auman, BS; Carolyn M. Petrie Huitema, MS CCRP; Kristin M. Zaterka-Baxter, RN BSN CCRP.
Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70) – Valerie Y. Chock, MD MS Epi; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Marian M. Adams, MD; Magdy Ismail, MD, MPH; Andrew W. Palmquist, RN; Melinda S. Proud, RCP; Elizabeth N. Reichert, MA CCRC, R. Jordan Williams, BA.
Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54) – Ivan D. Frantz III, MD; John M. Fiascone, MD; Brenda L. MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN BSN.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32) – Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Tara McNair, RN BSN; Meredith Estes, RN BSN; Kelli Hagood, RN BSN.
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; 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; David Kaegi, MD; Maynard R. Rasmussen, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Wade Rich, BSHS RRT.
University of Iowa, Mercy Medical Center, and Sanford Health (UG1 HD53109, M01 RR59, UL1 TR442) – Tarah T. Colaizy, MD MPH; Michelle L. Baack, MD; Dan L. Ellsbury, MD; John A. Widness, MD; Jane E. Brumbaugh, MD; Karen J. Johnson, RN BSN; Megan M. Henning, RN; Chelsey Elenkiwich, RN BSN; Claire A. Goeke, RN; Megan Broadbent, RN BSN; Laurie A. Hogden, MD; Jonathan M. Klein, MD; John M. Dagle, MD PhD; Mendi L. Schmelzel, RN MSN; Donia B. Bass, RNC-NC; Jacky R. Walker, RN; Tracy L. Tud, RN.
University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587) – Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett-Thomas, RN MSN.
University of New Mexico Health Sciences Center (U10 HD53089, M01 RR997) – Kristi L. Watterberg, MD; Janell Fuller, MD; Robin K. Ohls, MD; Sandra Sundquist Beauman, MSN RNC-NIC; Conra Backstrom Lacy, RN; Carol H. Hartenberger, MPH RN; Mary Ruffaner Hanson, RN BSN; Elizabeth Kuan, RN BSN.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (U10 HD68244) – Eric C. Eichenwald, MD; Sara B. DeMauro, MD MSCE; Barbara Schmidt, MD MSc; Haresh Kirpalani, MB MSc; Soraya Abbasi, MD; Christine Catts, CRNP; Aasma S. Chaudhary, BS RRT; Dara M. Cucinotta, RN; Sarvin Ghavam, MD; Toni Mancini, RN BSN CCRC; Jonathan Snyder, RN BSN.
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) – Carl T. D’Angio, MD; Ronnie Guillet, MD PhD; Dale L. Phelps, MD; Anne Marie Reynolds, MD MPH; Satyan Lakshminrusimha, MD; Alison Kent, MD; Kyle Binion, BS; Melissa Bowman, MSN; Cassandra A. Horihan, MS; Rosemary Jensen; Julianne Hunn, BS; Jennifer Donato, BS; Stephanie Guilford, BS; Emily Li, BA; Deanna Maffett, RN; Constance Orme; Diane Prinzing; Linda J. Reubens, RN CCRC; Daisy Rochez, BS MHA; Mary Rowan, RN; Premini Sabaratnam, MPH; Holly I.M. Wadkins, MA; Ashley Williams, MSEd; Karen Wynn, RN; Erica Burnell, RN; Rachel Jones; Michael G. Sacilowski, MAT CCRC; Ann Marie Scorsone, MS CCRC.
University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – Myra H. Wyckoff, MD; Luc P. Brion, MD; Pablo J. Sánchez, MD; Walid A. Salhab, MD; Charles R. Rosenfeld, MD; Diana M. Vasil, MSN BSN RNC-NIC; Lijun Chen, PhD RN; Maria M. DeLeon, RN BSN; Frances Eubanks, RN BSN; Alicia Guzman; Gaynelle Hensley, RN; Lizette E. Lee, RN; Melissa H. Leps, RN; Nancy A. Miller, RN; Janet S. Morgan, RN; Lara Pavageau, MD; Pollieanna Sepulveda, RN.
University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, McKay-Dee Hospital, Utah Valley Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64, UL1 RR25764) – Bradley A. Yoder, MD; Mariana Baserga, MD MSCI; Roger G. Faix, MD; Carrie A. Rau, RN BSN CCRC; Karie Bird, RN BSN; Jill Burnett, RNC BSN; Susan Christensen, RN; Brandy Davis, RN; Jennifer O. Elmont, RN BSN; Jennifer J. Jensen, RN BSN; Manndi C. Loertscher, BS CCRP; Trisha Marchant, RNC; Earl Maxson, RN CCRN; Kandace McGrath; Stephen D. Minton, MD; Karen A. Osborne, RN BSN CCRC; Melody Parry, RN; Susan T. Schaefer, RN BSN RRT; Mark J. Sheffield, MD; Cynthia Spencer, RNC BSN; Kimberlee Weaver-Lewis, RN MS; Kathryn D. Woodbury, RN BSN; Karen Zanetti, RN.
Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (U10 HD40498, M01 RR7122) – T. Michael O’Shea, MD MPH; Nancy Peters, RN.
Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385) – Seetha Shankaran, MD; Girija Natarajan, MD; Sanjay Chawla, MD; Beena G. Sood, MD; Athina Pappas, MD; John Barks, MD; Rebecca Bara, RN BSN; Kirsten Childs, RN BSN; Mary Christensen, BA RRT; Bogdan Panaitescu, MD; Stephanie A. Wiggins, MS; Diane White, RRT CCRP.
Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, ULTR142, M01 RR125) – Richard A. Ehrenkranz, MD (deceased); Harris Jacobs, MD; Patricia Cervone, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Janet Taft, RN BSN.
This manuscript was drafted and prepared solely by the authors. All named persons on this manuscript agree to its submission and publication in its current form. The data within this manuscript and the conclusions drawn from it will not and have not been presented at a meeting. All authors grant permission to post an earlier version on a pre-print server.
Abbreviations
- ANS
antenatal corticosteroids
- ICH
intracranial hemorrhage
- PVL
periventricular leukomalacia
Footnotes
Conflicts of Interest The authors have no conflicts of interest to disclose.
Declarations
Disclosures WA Carlo is on the board of MEDNAX, Inc; The authors report no other relationships or activities that could appear to have influenced the submitted work.
Ethical Approval
The UAB Institutional Review Board for Human Use approved this study (IRB-000330023) on November 16, 2020.
Access to Data: Ms. Hansen and Dr. Das had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data Sharing
Will individual participant data be available (including data dictionaries)?
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
What data in particular will be shared?
The NRN complies with the NIH Data Sharing Policy and the NIH Genomic Data Sharing Policy.
What other documents will be available?
For datasets that have not been previously released in public databases, release of NRN datasets requires the approval of the NRN Steering Committee and a signed Data Use Agreement.
When will data be available (start and end dates)?
Data will be made available as approved under an approved Data Use Agreement with the NRN Data Coordinating Center.
How will data be shared (including with whom, for what types of analyses, and by what mechanism)?
To receive datasets that have not been previously released in public databases, requesting investigators must:
Provide the necessary funds to reimburse the NRN Data Coordinating Center for its efforts towards producing the requested public use datasets.
Have IRB or Ethics Committee approval or documentation of non-human subjects research determination/exemption for the proposed study prior to receiving any human subject data.
Once a request is approved, sign a Data Use Agreement with the NRN Data Coordinating Center. The agreement specifies that the dataset is only to be used for the specific purpose listed in the agreement. The authorized investigator will not copy or distribute it to other people without permission from the NRN Steering Committee. If the recipient moves to a new institution, then a new agreement must be completed.
Agree to protect subject confidentiality and not seek to, or facilitate mechanisms leading to, the identification of individual subjects who participated in the study.
The external requestor is asked to acknowledge the use of the NICHD Neonatal Research Network materials in all relevant applications, presentations, and publications, along with a disclaimer that: “The contents of this report represent the views of the authors and do not represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network or the National Institutes of Health.” This statement will be placed in the acknowledgement section unless journals request its placement elsewhere in the paper.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Will individual participant data be available (including data dictionaries)?
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
What data in particular will be shared?
The NRN complies with the NIH Data Sharing Policy and the NIH Genomic Data Sharing Policy.
What other documents will be available?
For datasets that have not been previously released in public databases, release of NRN datasets requires the approval of the NRN Steering Committee and a signed Data Use Agreement.
When will data be available (start and end dates)?
Data will be made available as approved under an approved Data Use Agreement with the NRN Data Coordinating Center.
How will data be shared (including with whom, for what types of analyses, and by what mechanism)?
To receive datasets that have not been previously released in public databases, requesting investigators must:
Provide the necessary funds to reimburse the NRN Data Coordinating Center for its efforts towards producing the requested public use datasets.
Have IRB or Ethics Committee approval or documentation of non-human subjects research determination/exemption for the proposed study prior to receiving any human subject data.
Once a request is approved, sign a Data Use Agreement with the NRN Data Coordinating Center. The agreement specifies that the dataset is only to be used for the specific purpose listed in the agreement. The authorized investigator will not copy or distribute it to other people without permission from the NRN Steering Committee. If the recipient moves to a new institution, then a new agreement must be completed.
Agree to protect subject confidentiality and not seek to, or facilitate mechanisms leading to, the identification of individual subjects who participated in the study.
The external requestor is asked to acknowledge the use of the NICHD Neonatal Research Network materials in all relevant applications, presentations, and publications, along with a disclaimer that: “The contents of this report represent the views of the authors and do not represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network or the National Institutes of Health.” This statement will be placed in the acknowledgement section unless journals request its placement elsewhere in the paper.