The administration of antenatal corticosteroids increased over the 10-year period but remained lower at the lower gestational ages. The ranges for sample size by year are 15 to 36 for 22 weeks' gestation, 85 to 140 for 23 weeks' gestation, 134 to 325 for 24 weeks' gestation, and 162 to 333 for 25 weeks' gestation.
Carlo WA, McDonald SA, Fanaroff AA, Vohr BR, Stoll BJ, Ehrenkranz RA, Andrews WW, Wallace D, Das A, Bell EF, Walsh MC, Laptook AR, Shankaran S, Poindexter BB, Hale EC, Newman NS, Davis AS, Schibler K, Kennedy KA, Sánchez PJ, Van Meurs KP, Goldberg RN, Watterberg KL, Faix RG, Frantz ID, Higgins RD, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network FT. Association of Antenatal Corticosteroids With Mortality and Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks' Gestation. JAMA. 2011;306(21):2348-2358. doi:10.1001/jama.2011.1752
Author Affiliations: Department of Pediatrics, University of Alabama, Birmingham (Drs Carlo and Andrews); Children's Hospital of Alabama, Birmingham (Drs Carlo and Andrews); Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina (Mr McDonald and Dr Wallace); Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio (Drs Fanaroff and Walsh and Ms Newman); Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island (Drs Vohr and Laptook); Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia (Dr Stoll and Ms Hale); Children's Healthcare of Atlanta, Atlanta, Georgia (Dr Stoll and Ms Hale); Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut (Dr Ehrenkranz); Statistics and Epidemiology Unit, RTI International, Rockville, Maryland (Dr Das); Department of Pediatrics, University of Iowa, Iowa City (Dr Bell); Department of Pediatrics, Wayne State University, Detroit, Michigan (Dr Shankaran); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (Dr Poindexter); Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California (Drs Davis and van Meurs); Lucile Packard Children's Hospital, Palo Alto, California (Drs Davis and van Meurs); Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio (Dr Schibler); Department of Pediatrics, University of Texas Medical School, Houston (Dr Kennedy); Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (Dr Sanchez); Department of Pediatrics, Duke University, Durham, North Carolina (Dr Goldberg); Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (Dr Watterberg); Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City (Dr Faix); Department of Pediatrics, Division of Newborn Medicine, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts (Dr Frantz); and Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland (Dr Higgins).
Context Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care.
Objective To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation.
Design, Setting, and Participants Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10 541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables.
Main Outcome Measures Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age.
Results Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]).
Conclusion Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.
Data from large neonatal databases document that infants born around the limits of viability have high mortality and morbidity rates,1- 3 which have not improved during recent years.4 Broad application of interventions proven to be effective at more advanced gestational ages, such as antenatal corticosteroids, may improve outcomes in these infants. A single course of antenatal corticosteroids given 24 hours to 7 days before birth to women in preterm labor at less than 34 weeks' gestation improves lung maturity and reduces neonatal problems, including respiratory distress syndrome, necrotizing enterocolitis, severe intraventricular hemorrhage, and death.5
However, there are limited data from high-quality studies on the effects of antenatal corticosteroids at 22 to 25 weeks' gestation. Two recent meta-analyses confirmed that published data do not demonstrate that antenatal corticosteroids improve outcomes at less than 26 weeks' gestation.5,6 However, the small number of infants born at gestational ages around the limits of viability and included in published trials limits these results.5,6 Furthermore, antenatal corticosteroid trials include almost no data on neurodevelopmental outcomes even though these immature infants are at high risk of severe neurodevelopmental impairment.7
In 1995, National Institutes of Health Consensus Conference8 participants concluded that “Because data from randomized controlled trials did not include infants below 24 weeks, the current recommendations are to administer antenatal corticosteroids as early as but not before 24 weeks.” The recent opinion of the Committee on Obstetric Practice of the American College of Obstetrics and Gynecologists9 states that sparse data exist on the efficacy of corticosteroid use “before the age of viability,” and thus such use before 24 weeks' gestation was not recommended. Similar recommendations are used worldwide.10,11 The limited data on the effectiveness of antenatal corticosteroids in very preterm deliveries has led to restriction in their use1,4,10,12,13 and international10 and regional1 practice variability, even though infants as immature as 22 and 23 weeks' gestation frequently receive intensive care.
This study was designed to determine if antenatal corticosteroid exposure in infants born at each gestational age from 22 to 25 weeks is associated with improvement in important outcomes, including the primary outcome of death or childhood neurodevelopmental impairment, using a large cohort of infants.
Infants born at any of the 23 National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1993, and December 31, 2009, were included if they were 22 to 25 weeks' gestation with a birth weight between 401 g and 1000 g. Gestational age was determined according to standard Neonatal Research Network definitions using the hierarchy of best obstetrical estimate14 over the best neonatal data estimate. Infants with congenital anomalies were included. Infants who died during the first 12 hours after birth without receiving delivery room resuscitation (no ventilation, intubation, or medications) were excluded from the primary analysis to make sure the results were not affected by postnatal restriction of care. Infants who died in the delivery room were included in a secondary analysis.
Infants were categorized as having been exposed to antenatal corticosteroids if their mother received 1 or more doses of dexamethasone or betamethasone or not exposed if their mother did not receive antenatal corticosteroids. Data on full or partial course of antenatal corticosteroids were collected but data on timing and dose were not available.
Trained research coordinators prospectively collected maternal and neonatal data according to common definitions.1 Sociodemographic and clinical data were collected until death, discharge home, or 120 days, whichever occurred first, including transfers to other hospitals, using hospital chart reviews. Race/ethnicity, which can alter the response to antenatal steroids, was recorded as self-selected by the mother from options defined by federally funded study guidelines. Maternal education level and insurance data were available except for children born between 1993 and 2001 and those who were not followed up. Data on language spoken were available only on infants who were followed up. Data on type of corticosteroid were collected starting in 2002. Chorioamnionitis data were collected starting in 2006.
All survivors were scheduled at 18 to 22 months' corrected age for a standardized comprehensive neurodevelopmental assessment that was performed by certified examiners,15 who were unaware of exposure to antenatal corticosteroids. Only neurodevelopmental assessments on infants born between 2003 and 2008 were included in this study.
This study was a secondary analysis of the Neonatal Research Network Hospital Generic Database and Follow-up protocols, which were approved by each center's institutional review board. Written informed consent was obtained for the follow-up protocol. In 3 centers, written or oral informed consent was obtained for the hospital database protocol, while in the other centers, waiver of consent was approved by the institutional review boards.
Hospital death was defined as death of an infant before discharge or by 120 days in those with longer initial hospitalizations. Mortality before follow-up was documented at 18 to 22 months' corrected age.16 Bronchopulmonary dysplasia was defined as continuous use of supplemental oxygen at 36 weeks' postmenstrual age. The physiological definition for bronchopulmonary dysplasia17 was not used. Intraventricular hemorrhage grade 3-4 was determined according to the classification by Papile et al.18 For infants born up to 2005, severe neurodevelopmental impairment at 18 to 22 months' corrected age was defined as 1 or more of the following: a Bayley II Mental Developmental Index score of less than 70 (>2 SDs below the mean for normal infants), a Bayley II Psychomotor Developmental Index score of less than 70, moderate to severe cerebral palsy, blindness (no useful vision in either eye), or deafness (functional hearing impairment with aids in both ears).15 For infants born after 2005, the Bayley III was used instead, and severe neurodevelopmental impairment was defined as 1 or more of the following: Bayley III cognitive composite score of less than 70, gross motor function level of 2 or greater, blindness (some or no useful vision in either eye), or deafness (functional hearing impairment).
Outcomes were analyzed by exposure or nonexposure to antenatal corticosteroids. The primary outcome measure was death or neurodevelopmental impairment at follow-up (18-22 months). Secondary outcome measures and subgroup analyses were prespecified. Secondary outcomes at hospital discharge included death, bronchopulmonary dysplasia, intraventricular hemorrhage grade 3-4 or periventricular leukomalacia (or both), necrotizing enterocolitis, and death plus each morbidity. Secondary outcomes at 18 to 22 months' corrected age included death, neurodevelopmental impairment, and the individual components of neurodevelopmental impairment. Subgroups were selected as potential effect modifiers based on published meta-analyses.5,6 Missing data were excluded; imputation was not used. Differences in categorical measures were analyzed with χ2 analyses. Within each week of gestational age, logistic regression models were used to estimate the relationship between antenatal corticosteroid administration and outcomes with adjustments made for maternal variables (age, marital status, race, diabetes, hypertension or preeclampsia, rupture of membranes >24 hours, antepartum hemorrhage, and delivery mode), multiple birth, sex, and center. A cohort effect was included in the follow-up data models to indicate Bayley II vs Bayley III assessments. To allow for changes in neonatal care over time and to assess whether the effect of antenatal corticosteroids was stable over time, additional logistic regression models were run adding adjustment for epoch (1993-1998, 1999-2003, 2004-2009) and statistical interaction between antenatal corticosteroids and epoch.
The study was designed to use all the data available in the Neonatal Research Network database to explore the association between antenatal corticosteroid use and outcomes. Formal power analysis and sample size estimates were not performed. SAS software version 9.2 (SAS Institute Inc) was used for all statistical analyses. Odds ratios (ORs) and 95% confidence intervals were estimated for binary outcomes. Two-sided P values of less than .05 indicated statistical significance. Adjustments for multiple comparisons were not done. A Kaplan-Meier survival analysis for age at death was performed. Interaction terms between antenatal corticosteroid use and gestational age were added to the models fitted to the entire data set to examine differences in the effect of antenatal corticosteroids by gestational age.
A total of 1848 infants (941 born at 22 weeks’ gestation, 684 at 23 weeks, 179 at 24 weeks, and 44 at 25 weeks) died in the first 12 hours after birth without receiving delivery room resuscitation and were excluded from the primary analyses. The study population consisted of 10 541 infants (range, 63-971 infants per center), of whom 7808 (74.1%) were born to mothers who received antenatal corticosteroids (Table 1). Of the 5691 infants born between 1993 and 2008 who survived to 18 to 22 months, 4924 (86.5%) had neurodevelopmental assessments. The highest percentage of missing data for hospitalization outcomes was for bronchopulmonary dysplasia (4.0%). For the primary outcome, the percentage of missing data was 10.3%. There was no difference in the birth weight of infants whose mothers received antenatal corticosteroids and in those whose mothers did not receive them but there were other baseline differences; the women who did not receive corticosteroids were more likely to be black, be 19 years old or younger, have a lower income, and have Medicaid coverage and were less likely to be married, have completed high school, or have a cesarean delivery (Table 1). The percentage of infants whose mothers received antenatal corticosteroids increased in the early to mid-1990s as research on antenatal corticosteroids in early gestation became known and the 1995 National Institutes of Health consensus was published. This occurred in all 4 gestational age subgroups but remained lower for the infants born at 22 and 23 weeks' gestation (Figure).
For the cohort as a whole, of the hospitalization outcomes, death (35.5% with exposure to antenatal corticosteroids vs 56.0% without exposure; adjusted OR [AOR], 0.58 [95% CI, 0.52-0.65]), intraventricular hemorrhage grade 3-4 or periventricular leukomalacia (or both) (19.2% with exposure to antenatal corticosteroids vs 27.6% without exposure; AOR, 0.67 [95% CI, 0.57-0.79]), and many of the composite outcomes were significantly lower in the infants whose mothers had received antenatal corticosteroids (Table 2). The lower hospital death rate was partially offset by a higher rate of bronchopulmonary dysplasia (60.3% with exposure to antenatal corticosteroids vs 54.0% without exposure; AOR, 1.43 [95% CI, 1.23-1.67]). Hospital death was lower in infants exposed to antenatal corticosteroids who were born at 23, 24, and 25 weeks' gestation (Table 2). The AOR for reduction in hospital death in the infants born at 22 weeks' gestation was in the range of those born at other weeks but the sample size was smaller and the confidence level wider, overlapping 1.0. The Kaplan-Meier survival analyses revealed that there was a significant association between exposure to antenatal corticosteroids and survival (eFigure). Death, intraventricular hemorrhage grade 3-4, or periventricular leukomalacia (or any of the 3) also was lower in those exposed to antenatal corticosteroids who were born at 23, 24, and 25 weeks' gestation but was not significantly lower in those born at 22 weeks' gestation. The rate of death or bronchopulmonary dysplasia (or both) was lower in the infants born at 23 weeks' gestation but bronchopulmonary dysplasia in survivors was higher in infants born at 24 and 25 weeks' gestation. Death or necrotizing enterocolitis was lower at all gestational ages, including at 22 weeks' gestation.
At the 18- to 22-month follow-up, the primary outcome of death or neurodevelopmental impairment was less frequent in those exposed to antenatal corticosteroids (AOR, 0.60; 95% CI, 0.53-0.69) as well as death (37.0% with exposure to antenatal corticosteroids vs 57.2% without exposure; AOR, 0.59 [95% CI, 0.53-0.65]), neurodevelopmental impairment (38.8% with exposure to antenatal corticosteroids vs 49.2% without exposure; AOR, 0.83 [95% CI, 0.70-0.99]), moderate to severe cerebral palsy (8.6% with exposure to antenatal corticosteroids vs 12.0% without exposure; AOR, 0.76 [95% CI, 0.59-0.98]), and psychomotor developmental index score of less than 70 (27.3% with exposure to antenatal corticosteroids vs 32.8% without exposure; AOR, 0.79 [95% CI, 0.65-0.96]) (Table 3). Intact survival (no death or neurodevelopmental impairment by follow-up) at 18 to 22 months was higher in infants whose mothers received antenatal corticosteroids (35.8% with exposure to antenatal corticosteroids vs 18.5% without exposure; AOR, 1.66 [95% CI, 1.46-1.90]). Death or neurodevelopmental impairment was less frequent in those who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]) (Table 3). Interaction analyses performed for both hospital and follow-up outcomes provided no evidence that the associations of antenatal corticosteroids with outcomes differed across the 23, 24, and 25 weeks' gestational age groups.
Subgroup analyses indicated that exposure to antenatal corticosteroids was associated with lower hospital mortality, lower mortality at 18 to 22 months, and lower mortality or neurodevelopmental impairment at 18 to 22 months in singleton and multiple births, partial and full antenatal corticosteroid treatment groups, betamethasone and dexamethasone treatment groups, infants of mothers with and without diabetes, all durations of rupture of membrane subgroups, infants of mothers with and without antepartum hemorrhage, those delivered vaginally and by cesarean section, males and females, infants not small for gestational age, and all racial/ethnic subgroups (Table 4; eTable 1 and eTable 2). These outcomes did not significantly differ by exposure to antenatal corticosteroids in the infants born small for gestational age. In infants born to mothers with hypertension or preeclampsia or eclampsia, exposure to antenatal corticosteroids was associated with lower hospital death and death by 18 to 22 months but there was no difference in death or neurodevelopmental impairment by 18 to 22 months. Neither epoch nor interaction between antenatal corticosteroids and epoch was significant in the models for the primary outcome of death or neurodevelopmental impairment, indicating the robustness of the results with regard to any temporal trends (eTable 3 and eTable 4).
The association of exposure to antenatal corticosteroids and lower mortality was even stronger when the 1848 early deaths during the first 12 hours after birth without receiving delivery room resuscitation were included in the analysis (eTable 5). In this analysis, exposure to antenatal corticosteroids in infants born at 22, 23, 24, and 25 weeks' gestation was associated with a statistically significant lower rate of death.
This multicenter observational study cohort is larger than all other reported cohorts of infants born at 22 to 25 weeks’ gestation combined and documents that exposure to antenatal corticosteroids was associated with lower mortality or neurodevelopmental impairment at 18 to 22 months in infants born at each week from 23 to 25 weeks’ gestation, even after adjustment for multiple potential confounders. A significant association was not found at 22 weeks' gestation; however, the 95% confidence intervals were wide and the power was limited. However, even though intact survival doubled with the administration of antenatal steroids in the entire cohort, it remained relatively low (36%).
The outcome of neurodevelopmental impairment and death after discharge in infants is unique because most previous studies have focused on hospital outcomes.
Multiple secondary outcomes measured during hospitalization and at 18 to 22 months also were significant, and no evidence was found to suggest that these associations with antenatal corticosteroids differed across the range from 23 through 25 weeks' gestation. Subgroup analyses indicated that these associations were significant in all subgroups at this early gestational age range, except in infants small for gestational age and in infants of mothers with hypertension, preeclampsia, or eclampsia. The lower mortality rate during hospitalization in infants exposed to antenatal corticosteroids was partially offset by a higher rate of bronchopulmonary dysplasia at the early gestational ages as reported by others,6 which may be due to the high rate of bronchopulmonary dysplasia in infants who would be expected to die if they were not exposed to antenatal corticosteroids.
These data addressed the most important neonatal outcomes using a large prospective database with a high follow-up rate and adjusted for multiple maternal and neonatal variables. However, there are limitations of the study that should be noted. Potential biases include that mothers who received antenatal corticosteroids and their infants were different on a number of characteristics than those who did not. Adjustments were made using logistic regression models for many maternal, infant, and perinatal center variables but not for all variables. In addition, we did not have data on some potential confounders such as whether women presenting late in labor who would not have been eligible for antenatal corticosteroids were more commonly in the group that did not receive them. It is unlikely that the results are due to confounding, but it is possible that there is some residual or unmeasured bias in the results due to baseline differences between the study groups.
Another limitation is that other aspects of obstetrical care are likely to affect neonatal survival in pregnancies around the limits of viability. Willingness to perform a cesarean section for fetal indications was associated with a lower rate of neonatal mortality in a multicenter prospective observational study that included 713 singleton infants with birth weights of 1000 g or less.19 We cannot exclude the possibility that willingness to perform a cesarean section or use of other therapies may have influenced outcomes. The cesarean section rate was higher in the group exposed to antenatal corticosteroids than in the group without exposure. However, it should be noted that more than one-third of the infants in the group without exposure to antenatal corticosteroids were delivered by cesarean section.
The possibility of postnatal treatment bias based on antenatal corticosteroid administration (eg, withholding postnatal therapies in infants whose mothers did not receive antenatal corticosteroids) cannot be excluded. To mitigate this effect, infants not receiving resuscitation who died within the first 12 hours after birth were excluded, but otherwise all live births were entered into the database, including infants who died in the delivery room. Nonetheless, obstetrical and neonatal care was provided at the discretion of clinicians and parents, and the frequency and intensity with which such care was applied varied among and within centers.
Because infants with birth weights of 400 g or less were excluded from the database, not all infants born at 22 to 25 weeks' gestation are included in this study. In addition, the primary outcome could not be determined in 10.3% of the infants, raising some concerns about validity. Data were not collected on the timing or dose of antenatal corticosteroid treatment, fetal monitoring, or length of maternal hospitalization before delivery so these could not be studied. Data were not collected on maternal complications but the large meta-analysis5 did not report important maternal adverse effects other than glucose intolerance in 1 study.
Data from randomized controlled trials of exposure to antenatal corticosteroids in infants born at less than 26 weeks' gestation are limited, and meta-analyses do not support or refute the benefits of exposure to antenatal corticosteroids at these early gestational ages.5,6 However, several reports of large series of infants exposed to antenatal corticosteroids and born at gestational ages around the limits of viability describe benefits. Treatment with antenatal corticosteroids was associated with reduced mortality to hospital discharge among 753 infants born at 22 to 23 weeks' gestation from 87 hospitals in Japan.20 However, the major neonatal morbidities were not affected and the data were only analyzed for the combined weeks. A population-based series of 705 infants born at less than 26 weeks' gestation showed that exposure to antenatal corticosteroids was associated with reductions in hospital mortality,21 severe motor disability, and low scores on the Mental Developmental Index.22 A study of 181 infants born at 23 weeks' gestation in 3 hospitals over a 10-year period reported reductions in mortality only for the infants exposed to a full course of antenatal corticosteroids.23 A study of 117 singleton infants exposed to a complete course of antenatal corticosteroids at less than 24 weeks' gestation and born at 23 to 25 weeks' gestation in a single hospital over a 10-year period revealed that corticosteroid administration was associated with reduction in mortality and severe intracranial hemorrhage.24 Other large multicenter studies have shown that antenatal corticosteroids were associated with decreased hospital mortality10,16,25 and severe disability13,26,27 in very preterm infants but have not focused the analysis on those born before 24 weeks' gestation. These patient series show that antenatal corticosteroids are associated with variable reductions in mortality and morbidities.
The current study showed large reductions in mortality with a multicenter database and extends the findings to include reductions in important in-hospital and follow-up morbidities. Furthermore, the reduction in adverse outcomes was observed in almost all patient subgroups. Thus, it is likely that the results of this study are generalizable to a broad population. Even though concern has been expressed about repeated courses of antenatal corticosteroids if started early during pregnancy,7 2 recent trials of repeated courses demonstrated no increased risk for neurodevelopmental impairment.28,29 Thus, concerns about repeated courses of antenatal steroids should not preclude the initial administration of antenatal steroids at a gestational age around the limits of viability.
In summary, antenatal corticosteroid therapy for mothers of infants born at 23, 24, and 25 weeks' gestation was associated with lower rates of both mortality and important morbidities, including a lower rate of death or severe neurodevelopmental impairment at 18 to 22 months' corrected age. These benefits were observed across subgroups without evidence that they differed across the ranges of gestational ages around the limits of viability. Despite their potential to improve outcomes, the administration of antenatal corticosteroids is not increasing at gestational ages around the limits of viability4 and remains substantially lower than at later gestational ages. Controlled trials could be performed to precisely determine the benefits of antenatal corticosteroids when administered this early but such trials will be difficult to perform. Initiation of antenatal corticosteroids may be considered starting at 23 weeks' gestation and later if the infant will be given intensive care because this therapy is associated with reduced mortality and morbidity.
Corresponding Author: Waldemar A. Carlo, MD, Department of Pediatrics, University of Alabama, 9380 Women and Infants Center, 1700 Sixth Ave S, Birmingham, AL 35249 (email@example.com).
Author Contributions: Dr Das and Mr McDonald had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Carlo, Fanaroff, Davis, Higgins.
Acquisition of data: Carlo, Fanaroff, Vohr, Stoll, Ehrenkranz, Bell, Walsh, Laptook, Shankaran, Poindexter, Hale, Newman, Schibler, Kennedy, Sánchez, van Meurs, Goldberg, Watterberg, Faix, Frantz.
Analysis and interpretation of data: Carlo, McDonald, Wallace, Das, Higgins.
Drafting of the manuscript: Carlo, McDonald.
Critical revision of the manuscript for important intellectual content: Carlo, McDonald, Fanaroff, Vohr, Stoll, Ehrenkranz, Andrews, Wallace, Das, Bell, Walsh, Laptook, Shankaran, Poindexter, Hale, Newman, Davis, Schibler, Kennedy, Sánchez, van Meurs, Goldberg, Watterberg, Faix, Frantz, Higgins.
Statistical analysis: McDonald, Wallace, Das.
Obtained funding: Carlo, Fanaroff, Stoll, Ehrenkranz, Das, Bell, Walsh, Laptook, Shankaran, Poindexter, Schibler, Kennedy, Sánchez, van Meurs, Goldberg, Faix, Frantz.
Administrative, technical, or material support: Carlo, Andrews, Wallace, Shankaran, Newman, Schibler, Sánchez, Goldberg, Higgins.
Study supervision: Carlo, Fanaroff, Stoll, Ehrenkranz, Poindexter, Schibler, Kennedy, Sánchez, Faix, Higgins.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Carlo reported that he is a board member of Mednax. Dr Sánchez reported that he received study funding from F. Hoffman-LaRoche Ltd and Astellas for his work on the Collaborative Antiviral Study Group. Dr van Meurs reported that she received consulting fees, honorarium, and equipment support from Ikaria; travel, accommodations, and meeting expenses paid for by Actelion and Ikaria; and payment from legal firms for expert testimony for various lawsuits. Dr Faix reported that he serves on a data and safety monitoring board and receives funding from Ikaria Biosynexus. No other authors reported disclosures.
Funding/Support: The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's Generic Database and Follow-up Studies.
Role of the Sponsor: The protocol was investigator-initiated but the NICHD's staff participated in the final study design and conduct of the study; interpretation of the data; and review and approval of the manuscript through the cooperative grant mechanism. Data collected at participating sites of the NICHD's Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study.
Investigators and Study Sites: Alan H. Jobe, MD, PhD, University of Cincinnati (NRN steering committee chair); University of Chicago, Pritzker School of Medicine (Michael S. Caplan, MD); Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (William Oh, MD, Bonnie Stephens, MD, Robert Burke, MD, Barbara Alksninis, PNP, Melinda Caskey, MD, Katharine Johnson, MD, Angelita M. Hensman, RN, BSN, Suzy Ventura, Victoria E. Watson, MS, CAS, Theresa M. Leach, MEd, CAES; grant U10 HD27904); Brigham and Women's Hospital, Children's Hospital Boston, Beth Israel Deaconess Medical Center, and Harvard Medical School (Ann R. Stark, MD, Kerri Fournier, RN, Stacy Dow, RN, Kimberly Gronsman Lee, MD, Colleen Driscoll; grants U10 HD34167, M01 RR2635, and M01 RR2172); Case Western Reserve University, Rainbow Babies & Children's Hospital (Deanne Wilson-Costello, MD, Bonnie S. Siner, RN; grants U10 HD21364 and M01 RR80); Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (Edward F. Donovan, MD, Kate Bridges, MD, Barbara Alexander, RN, Jean Steichen, MD, Kimberly A. Yolton, PhD, Cathy Grisby, BSN, CCRC, Holly L. Mincey, RN, BSN, Jody Hessling, RN, Marcia Worley Mersmann, RN, CCRC, Teresa L. Gratton, PA; grants U10 HD27853 and M01 RR8084); Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (C. Michael Cotten, MD, MHS, Ricki Goldstein, MD, Kathy J. Auten, MSHS, Kimberley A. Fisher, PhD, FNP-BC, IBCLC, Katherine A. Foy, RN, Sandra Grimes, RN, BSN, Melody Lohmeyer, RN; grants U10 HD40492 and M01 RR30); Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (David P. Carlton, MD, Lucky Jain, MD, Ira Adams-Chapman, MD; grants U10 HD27851, M01 RR39, and UL1 RR25008); Eunice Kennedy Shriver National Institute of Child Health and Human Development (Linda L. Wright, MD, Stephanie Wilson Archer, MA, Elizabeth M. McClure, MEd); Floating Hospital for Children at Tufts Medical Center (Elisabeth C. McGowan, MD, Brenda L. MacKinnon, RNC, Anne Furey, MPH, Ellen Nylen, RN, BSN; grants U10 HD53119 and M01 RR54); Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (James A. Lemons, MD, Anna M. Dusick, MD, Diana D. Appel, RN, BSN, Dianne E. Herron, RN, Lucy C. Miller, RN, BSN, CCRC, Leslie Dawn Wilson, BSN, CCRC, Leslie Richard, RN; grants U10 HD27856, M01 RR750, and UL1 RR25761); RTI International (W. Kenneth Poole, PhD, Jeanette O’Donnell Auman, BS, Margaret Cunningham, BS, CCRP, Betty K. Hastings, Carolyn M. Petrie Huitema, MS, CCRP, Elizabeth M. McClure, MEd, Jamie E. Newman, PhD, MPH, James W. Pickett II, BS, Kristin M. Zaterka-Baxter, RN, BSN, CCRP; grant U10 HD36790); Stanford University, California Pacific Medical Center, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital (David K. Stevenson, MD, Susan R. Hintz, MD, MS, Epi, Marian M. Adams, MD, Barry E. Fleisher, MD, Jean G. Kohn, MD, MPH, Robert D. Stebbins, MD, Hali Weiss, MD, Joan M. Baran, PhD, Barbara Bentley, PhD, Lori Bond, PhD, Ginger K. Brudos, PhD, Elizabeth Bruno, PhD, Maria Elena DeAnda, PhD, Julie Lee-Ancajas, PhD, Renee P. Pyle, PhD, Nicholas St John, PhD, M. Bethany Ball, BS, CCRC, Anne M. DeBattista, RN, PRP, Melinda S. Proud, RCP; grants U10 HD27880, M01 RR70, and UL1 RR25744); University of Alabama at Birmingham Health System and Children's Hospital of Alabama (Namasivayam Ambalavanan, MD, Monica V. Collins, RN, BSN, MaEd, Shirley S. Cosby, RN, BSN, Myriam Peralta-Carcelen, MD, Vivien Phillips, RN, BSN, Fred J. Biasini, PhD, Reed Dimmitt, MD, David Randolph, MD, PhD; grants U10 HD34216 and M01 RR32); University of California–San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (Neil N. Finer, MD, Maynard R. Rasmussen, MD, Paul R. Wozniak, MD, Yvonne E. Vaucher, MD, MPH, Kathy Arnell, RNC, Renee Bridge, RN, Clarence Demetrio, RN, Martha G. Fuller, RN, MSN, Chris Henderson, RCP, CRTT, Wade Rich, BSHS, RRT; grant U10 HD40461); University of Iowa Children's Hospital (John A. Widness, MD, Michael J. Acarregui, MD, Karen J. Johnson, RN, BSN, Diane L. Eastman, RN, CPNP, MA; grants U10 HD53109, M01 RR59, and UL1 RR24979); University of Miami, Holtz Children's Hospital (Shahnaz Duara, MD, Charles R. Bauer, MD, Ruth Everett-Thomas, RN, MSN, Amy Mur Worth, RN, MS, Kasey Hamlin-Smith, PhD, Michelle Berkovits, PhD, Silvia M. Frade Eguras, BA, Mary Allison, RN; grant U10 HD21397); University of New Mexico Health Sciences Center (Lu-Ann Papile, MD, Janell Fuller, MD, Jean Lowe, PhD, Conra Backstrom Lacy, RN, Rebecca Montman, BSN; grants U10 HD53089 and M01 RR997); University of Rochester Medical Center, Golisano Children's Hospital (Dale L. Phelps, MD, Gary Myers, MD, Diane Hust, RN, PNP, Linda J. Reubens, RN, CCRC, Erica Burnell, RN, Rosemary L. Jensen, Mary Rowan, RN, Kelley Yost, PhD, Lauren Zwetsch, RN, MS, PNP, Julie Babish Johnson, MSW, Emily Kushner, MA, Cassandra A. Horihan, MS, Joan Merzbach, LMSW (grants U10 HD40521, M01 RR44, and UL1 RR24160); University of Tennessee Health Science Center (Sheldon B. Korones, MD, Henrietta S. Bada, MD, Marilyn G. Williams, LCSW, Kimberly Yolton, PhD; grant U10 HD21415); University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas (Charles R. Rosenfeld, MD, Walid A. Salhab, MD, Jon E. Tyson, MD, MPH, Roy J. Heyne, MD, Luc P. Brion, MD, Alicia Guzman, Jackie F. Hickman, RN, Nancy A. Miller, RN, Diana M. Vasil, RNC-NIC, Lizette E. Torres, RN, Janet S. Morgan, RN, Cathy Twell Boatman, MS, CIMI; grants U10 HD40689 and M01 RR633); 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 (Jon E. Tyson, MD, MPH, Esther G. Akpa, RN, BSN, Magda Cedillo, Patricia Ann Orekoya, RN, BSN, Susan E. Dieterich, PhD, Patricia W. Evans, MD, Claudia I. Franco, RNC, MSN, Charles E. Green, PhD, Beverly Foley Harris, RN, BSN, Margarita Jiminez, MD, MPH, Terri L. Major-Kincade, MD, MPH, Anna E. Lis, RN, BSN, Sarah C. Martin, RN, BSN, Georgia E. McDavid, RN, Brenda H. Morris, MD, M. Layne Poundstone, RN, BSN, Stacey Reddoch, BA, Saba Khan Siddiki, MD, Maegan C. Simmons, RN, Patti L. Pierce Tate, RCP, Laura L. Whitely, MD, Sharon L. Wright, MT [ASCP]; grant U10 HD21373); University of Utah University Hospital, LDS Hospital, and Primary Children's Medical Center (Bradley A. Yoder, MD, Karen A. Osborne, RN, BSN, CCRC, Jennifer J. Jensen, RN, BSN, Cynthia Spencer, RNC, Kimberlee Weaver-Lewis, RN, BSN, Jill Burnett, RNC, Shawna Baker, RN; grants U10 HD53124, M01 RR64, and UL1 RR25764); Wake Forest University Baptist Medical Center, Brenner Children's Hospital, and Forsyth Medical Center (T. Michael O’Shea, MD, MPH, Robert Dillard, MD, Nancy J. Peters, RN, CCRP, Barbara Jackson, RN, BSN; grants U10 HD40498 and M01 RR7122); Wayne State University, Hutzel Women's Hospital, and Children's Hospital of Michigan (Athina Pappas, MD, Yvette R. Johnson, MD, MPH, Virginia Delaney-Black, MD, MPH, Rebecca Bara, RN, BSN, Geraldine Muran, RN, BSN, Deborah Kennedy, RN, BSN, Laura A. Goldston, MA; grant U10 HD21385); Yale University, Yale-New Haven Children's Hospital, and Bridgeport Hospital (Harris Jacobs, MD, Linda C. Mayes, MD, Patricia Cervone, RN, Patricia Gettner, RN, Monica Konstantino, RN, BSN, JoAnn Poulsen, RN, Elaine Romano, MSN, Janet Taft, RN, BSN, Joanne Williams, RN, BSN, Nancy L. Close, PhD, Walter S. Gilliam, PhD, Christine G. Butler, MD, Sheila Greisman, RN; grants U10 HD27871, M01 RR125, M01 RR6022, and UL1 RR24139).
Online-Only Material: The Author Video Interview is available here.
Additional Contributions: We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.