Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation

doi:10.1001/jama.2011.1752

JAMA. Author manuscript; available in PMC 2013 February 6.

Published in final edited form as:

JAMA. 2011 December 7; 306(21): 2348–2358.

doi: 10.1001/jama.2011.1752

PMCID: PMC3565238

NIHMSID: NIHMS432430

Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation

Waldemar A. Carlo, MD,¹ Scott A. McDonald, BS,² Avroy A. Fanaroff, MD,³ Betty R. Vohr, MD,⁴ Barbara J. Stoll, MD,⁵ Richard A. Ehrenkranz, MD,⁶ William W. Andrews, PhD, MD,¹ Dennis Wallace, PhD,² Abhik Das, PhD,⁷ Edward F. Bell, MD,⁸ Michele C. Walsh, MD, MS,³ Abbot R. Laptook, MD,⁴ Seetha Shankaran, MD,⁹ Brenda B. Poindexter, MD, MS,¹⁰ Ellen C. Hale, RN, BS, CCRC,⁵ Nancy S. Newman, RN,³ Alexis S. Davis, MD, MS, Epi,¹¹ Kurt Schibler, MD,¹² Kathleen A. Kennedy, MD, MPH,¹³ Pablo J. Sanchez, MD,¹⁴ Krisa P. Van Meurs, MD,¹¹ Ronald N. Goldberg, MD,¹⁵ Kristi L. Watterberg, MD,¹⁶ Roger G. Faix, MD,¹⁷ Ivan D. Frantz, III, MD,¹⁸ and Rosemary D. Higgins, MD¹⁹, for the Eunice Kennedy ShriverNational Institute of Child Health and Human Development Neonatal Research Network

¹Department of Pediatrics, University of Alabama at Birmingham and Children’s Hospital of Alabama, Birmingham, AL

²Statistics and Epidemiology Unit, RTI International, Research Triangle Park, NC

³Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, OH

⁴Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, RI

⁵Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA

⁶Department of Pediatrics, Yale University School of Medicine, New Haven, CT

⁷Statistics and Epidemiology Unit, RTI International, Rockville, MD

⁸Department of Pediatrics, University of Iowa, Iowa City, IA

⁹Department of Pediatrics, Wayne State University, Detroit, MI

¹⁰Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN

¹¹Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford, University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, CA

¹²Department of Pediatrics, University of Cincinnati, Cincinnati, OH

¹³Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX

¹⁴Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX

¹⁵Department of Pediatrics, Duke University, Durham, NC

¹⁶Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM

¹⁷Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City, UT

¹⁸Department of Pediatrics, Division of Newborn Medicine, Floating Hospital for Children, Tufts Medical Ctr., Boston, MA

¹⁹Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD

Corresponding Author: Waldemar A. Carlo, M.D., Department of Pediatrics, University of Alabama at Birmingham, 9380 Women and Infants Center, 1700 6^th Avenue South, Birmingham, AL 35249-7335, Phone: (205) 934-4680, Fax: (205) 934-3100, Email: wcarlo/at/peds.uab.edu

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Abstract

Context

Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24–34 weeks gestational age, but not before 24 weeks because of lack of data. However, many infants born before 24 weeks are provided intensive care now.

Objective

To determine if antenatal corticosteroids are associated with improvement in major outcomes in infants born at 22 and 23 weeks.

Design, Setting, Participants

Data for this cohort study were collected prospectively on 401–1000 gram inborn infants (N=10,541) of 22–25 weeks gestation born between 1993–2009 at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4,924 (86.5%) of the infants born in 1993–2008 who survived to 18–22 months. Logistic regression models generated adjusted odds ratios, controlling for maternal and neonatal variables.

Main Outcome Measures

Mortality and neurodevelopmental impairment at 18–22 months corrected age

RESULTS

Death or neurodevelopmental impairment at 18–22 months was lower for infants whose mothers received antenatal corticosteroids born at 23 weeks (antenatal corticosteroids, 83.4% vs no antenatal corticosteroids, 90.5%; adjusted odds ratio 0.58; 95% CI, 0.42–0.80), at 24 weeks (antenatal corticosteroids, 68.4% vs no antenatal corticosteroids, 80.3%; adjusted odds ratio 0.62; 95% CI, 0.49–0.78), and at 25 weeks (antenatal corticosteroids, 52.7% vs no antenatal corticosteroids, 67.9%; adjusted odds ratio 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids, 90.2% vs no antenatal corticosteroids, 93.1%; adjusted odds ratio 0.80; 95% CI, 0.29–12.21). Death by 18–22 months, hospital death, death/intraventricular hemorrhage/periventricular leukomalacia, and death/necrotizing enterocolitis were significantly lower for infants born at 23, 24, and 25 weeks gestational age if the mothers had received antenatal corticosteroids but the only outcome significantly lower at 22 weeks was death/necrotizing enterocolitis (antenatal corticosteroids, 73.5% vs no antenatal corticosteroids, 84.5%; adjusted odds ratio 0.54; 95% CI, 0.30–0.97).

CONCLUSIONS

Among infants born at 23–25 weeks gestation, use of antenatal corticosteroids compared to non-use was associated with a lower rate of death or neurodevelopmental impairment at 18–22 months.

Keywords: prematurity, infant mortality, neonatal intensive care, neurodevelopmental impairment, lung maturation, limits of viability

INTRODUCTION

Data from large neonatal databases document that infants born around the limits of viability have high mortality and morbidity rates^(1,2,3) that 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. 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^(5,6). However, the small number of infants born at gestational ages around the limits of viability 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 Institute of Health Consensus Conference⁽⁸⁾ 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 Gynecologists⁽⁹⁾ states that sparse data exist on the efficacy of corticosteroid use “before the age of viability”, and thus such use before 24 weeks was not recommended. Similar recommendations are used worldwide^(10,11). The limited data on effectiveness of antenatal corticosteroids in very preterm deliveries has led to restriction in their use^{(1,4,10,12,13)} and international⁽¹⁰⁾ and regional⁽¹⁾ practice variability, even though infants as immature as 22 and 23 weeks frequently receive intensive care.

This study was designed to determine if antenatal corticosteroid exposure in infants born at each gestational age week 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.

METHODS

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 and had a birth weight of 401–1000 grams. Gestational age was determined according to standard Neonatal Research Network definitions using the hierarchy of best obstetrical estimate⁽¹⁴⁾ 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 into the “antenatal corticosteroid group” if their mother received 1 or more doses of antenatal corticosteroids (dexamethasone or betamethasone) and the “no antenatal corticosteroid group” 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.

Data Collection

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 infants born between 1993–2001 and infants not followed. Data on language spoken were available only on followed infants. Data on type of corticosteroids were collected starting in 2002. Chorioamnionitis data were collected starting in 2006. All survivors were scheduled at 18–22 months corrected age for a standardized comprehensive neurodevelopmental assessment that was performed by certified examiners⁽¹⁵⁾ 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.

Definitions

Hospital death was defined as death of an infant before discharge or by 120 days in those with longer initial hospitalization. Mortality before follow-up was documented at 18–22 months corrected age⁽¹⁶⁾. Bronchopulmonary dysplasia was defined as continuous use of supplemental oxygen at 36 weeks postmenstrual age. The physiologic definition for bronchopulmonary dysplasia ⁽¹⁷⁾ was not used, as it was implemented in 2003. Intraventricular hemorrhage grade 3–4 was determined according to the classification of Papile⁽¹⁸⁾. For infants born up to 2005, severe neurodevelopmental impairment at 18–22 months corrected age was defined as 1 or more of the following: a Bayley II Mental Developmental Index < 70 (> 2 standard deviations below the mean for normal infants), a Bayley II Psychomotor Developmental Index < 70, moderate-severe cerebral palsy, blindness (blind with 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 one or more of the following: Bayley III cognitive composite score < 70, gross motor function level 2 or greater, blindness (blind with some or little useful vision in either eye), or deafness (functional hearing impairment).

Statistical Analyses

Outcomes were analyzed by antenatal corticosteroid group. The primary outcome measure was death or neurodevelopmental impairment at follow-up (18–22 months). Secondary outcome measures and subgroup analyses were pre-specified. Secondary outcomes at hospital discharge included death, bronchopulmonary dysplasia, intraventricular hemorrhage grade 3–4 and/or periventricular leukomalacia, necrotizing enterocolitis, and death plus each morbidity.

Secondary outcomes at 18–22 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). Imputation was not used for missing data. Differences in categorical measures were analyzed with X² 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/preeclampsia, rupture of membranes >24 hours, antepartum hemorrhage, and delivery mode), multiple birth, gender, and center. A cohort effect was included in the follow-up data models to indicate Bayley II versus 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 corticosteroids and outcomes. Formal power analysis and sample size estimates were not performed. SAS software version 9.2 was used for all analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for binary outcomes. Two-sided P values of less than 0.05 were considered to indicate 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 to examine differences in the effect of antenatal corticosteroids by gestational age.

RESULTS

A total of 1848 infants (941 at 22 weeks, 684 at 23 weeks, 179 at 24 weeks, and 44 at 25 weeks) who died in the first 12 hours after birth without receiving delivery room resuscitation were excluded from the primary analyses. The study population consisted of 10,541 infants (range of 63 to 971 infants per center), 7,808 (74.1%) of whom were born to mothers who received antenatal corticosteroids (Table 1). Of the 5,691 infants born between 1993 and 2008 who survived to 18–22 months, 4,924 (86.5%) had neurodevelopmental assessments. The highest percent of missing data for hospitalization outcomes was for bronchopulmonary dysplasia (4.0%). For the primary outcome, the percent of missing data was 10.3%. There was no difference in the birth weight of infants whose mothers received antenatal corticosteroids and those whose mothers did not receive them but there were other baseline differences; those who did not receive corticosteroids were more likely to be black, 19 years old or younger, have a lower income, and be on Medicaid and were less likely to be married, have completed high school, or have a cesarean section (Table 1). The percentage of infants whose mothers received antenatal corticosteroids increased following the 1995 National Institutes of Health consensus in the 4 gestational age subgroups but remained lower for the 22 and 23 week infants (Figure 1).

Table 1

Infant/Maternal Characteristics of Infants 22 to 25 Weeks Gestation by Antenatal Corticosteroid Treatment

Figure 1

Frequency of exposure of antenatal corticosteroids by gestational age and year of birth. The administration of antenatal corticosteroids increased over the 10 year period but remained lower at the lower gestational ages. Denominators for each data point (more ...)

For the cohort as a whole, of the hospitalization outcomes, hospital death (antenatal corticosteroids, 35.5% vs no antenatal corticosteroids, 56.0%; adjusted OR 0.58; 95% CI, 0.52–0.65), intraventricular hemorrhage 3–4 and/or periventricular leukomalacia (antenatal corticosteroids, 19.2% vs no antenatal corticosteroids, 27.6%; adjusted OR 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 (antenatal corticosteroids, 60.3% vs no antenatal corticosteroids, 54.0%; adjusted OR 1.43; 95% CI, 1.23–1.67). Hospital death was lower in the antenatal corticosteroid group at 23, 24, and 25 weeks (Table 2). The adjusted OR for reduction in hospital death in the 22 week infants was in the range of those 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 antenatal corticosteroid use and survival (eFigure 1). Death and/or intraventricular hemorrhage grade 3–4 and/or periventricular leukomalacia was also lower in the antenatal corticosteroid groups at 23, 24, and 25 weeks but was not significantly lower at 22 weeks. The rate of death and/or bronchopulmonary dysplasia was lower in the 23 week infants but bronchopulmonary dysplasia in survivors was higher at 24 and 25 weeks. Death or necrotizing enterocolitis was lower at all gestational ages, including at 22 weeks.

Table 2

Hospital Outcomes of Infants 22 to 25 Weeks Gestation by Antenatal Corticosteroid Treatment

In the overall group at 18–22 months follow up, the primary outcome, death or neurodevelopmental impairment, was less frequent in the antenatal corticosteroid group (adjusted OR 0.60; 95% CI, 0.53–0.69), as were death (antenatal corticosteroids, 37.0% vs no antenatal corticosteroids, 57.2%; adjusted OR 0.59; 95% CI, 0.53–0.65), neurodevelopmental impairment (antenatal corticosteroids, 38.8% vs no antenatal corticosteroids, 49.2%; adjusted OR 0.83; 95% CI, 0.70–0.99), moderate-severe cerebral palsy (antenatal corticosteroids, 8.6% vs no antenatal corticosteroids, 12.0%; adjusted OR 0.76; 95% CI, 0.59–0.98), and psychomotor developmental index less than 70 (antenatal corticosteroids, 27.3% vs no antenatal corticosteroids, 32.8%; adjusted OR 0.79; 95% CI, 0.65–0.96) (Table 3). Intact survival (no death or neurodevelopmental impairment by follow-up) at 18–22 months was higher in infants whose mothers received antenatal corticosteroids (antenatal corticosteroids, 35.8% vs no antenatal corticosteroids, 18.5% for the full cohort; adjusted OR1.66; 95% CI. 1.46–1.90). Death or neurodevelopmental impairment was less frequent in the antenatal corticosteroid groups at 23 weeks (antenatal corticosteroids: 838/1,005 [83.4%] vs no antenatal corticosteroids: 676/747 [90.5%]; adjusted OR 0.58; 95% CI, 0.42–0.80), 24 weeks (antenatal corticosteroids: 1,711/2502 [68.4%] vs no antenatal corticosteroids: 559/696 [80.3%]; adjusted OR 0.62; 95% CI, 0.49–0.78), and 25 weeks (antenatal corticosteroids: 1,510/2,865 [52.7%] vs no antenatal corticosteroids: 451/664 [67.9%]; adjusted OR 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids: 101/112 [90.2%] vs no antenatal corticosteroids: 243/261 [93.1%]; adjusted OR 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 week gestational age groups.

Table 3

Outcomes by 18–22 Months Corrected Age of Infants 22 to 25 Weeks Gestation by Antenatal Corticosteroid Treatment for 1993–2008 Births

Subgroup analyses indicated that antenatal corticosteroids were associated with lower hospital mortality, lower mortality at 18–22 months, and lower mortality/neurodevelopmental impairment at 18–22 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, non-small for gestational age infants, and all racial/ethnic subgroups (Table 4 and eTables 1 and 2). These outcomes did not significantly differ by receipt of antenatal corticosteroids in the small for gestational age infants. In infants born to mothers with hypertension or preeclampsia/eclampsia, antenatal corticosteroids were associated with lower hospital death and death by 18–22 months but there was no difference in death or neurodevelopmental impairment by 18–22 months. Neither epoch nor antenatal corticosteroids-epoch interaction was significant in the models for the primary outcome of death or neurodevelopmental impairment, indicating the robustness of the results with regards to any temporal trends.

Table 4

Mortality or Severe Neurodevelopment Impairment by 18–22 Months of Infants by Antenatal Corticosteroid Treatment for 1993–2008 Births - Subgroup Analysis

The association of 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 3). In this analysis, use of antenatal corticosteroids at 22, 23, 24, and 25 weeks was associated with a statistically significant lower rate of death.

DISCUSSION

This multicenter observational study cohort is larger than all other reported 22 to 25 week cohorts together and documents that exposure to antenatal corticosteroids was associated with lower mortality or neurodevelopmental impairment at 18–22 months in infants born at each week from 23 to 25 weeks even after adjustment for multiple potential confounders. However, even though intact survival doubled with the administration of antenatal steroids, it remained relatively low (36%). The outcome of neurodevelopmental impairment and death after discharge in infants is unique as most previous studies have focused on hospital outcomes. Multiple secondary outcomes measured during hospitalization and at 18–22 months were also significant. No evidence was found to suggest that the associations with antenatal corticosteroids differed across the range from 23 to 25 weeks gestational age. Subgroup analyses indicated that these associations were significant in all subgroups at this early gestational age range, except in the small for gestational age infants and in infants of mothers with hypertension or preeclampsia/eclampsia. The lower mortality rate during hospitalization in the antenatal corticosteroid group was partially offset by a higher rate of bronchopulmonary dysplasia as reported by others at the early gestational ages,⁽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 addressed. 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 center variables but not all. 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 1000 grams or less ⁽¹⁹⁾. We cannot exclude the possibility that willingness to perform a cesarean section or use other therapies may have influenced outcomes. The cesarean section rate was higher in the antenatal corticosteroids group than in the no antenatal corticosteroids group. However, it should be noted that over one third of the infants in the no antenatal corticosteroids group were delivered by cesarean section.

The possibility of postnatal treatment bias based on antenatal corticosteroid administration (e.g. 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 in 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 400 grams or less were excluded from the database, not all 22 to 25 week infants 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-analysis did not report important maternal side effects other than glucose intolerance in one study ⁽⁵⁾.

Data from randomized controlled trials of antenatal corticosteroids in infants born at less than 26 weeks are limited, and meta-analyses do not support or refute the benefits of 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. Antenatal corticosteroid treatment was associated with reduced mortality to discharge among 753 infants born at 22 to 23 weeks from 87 hospitals in Japan⁽²⁰⁾. However, the major neonatal morbidities were not affected and they analyzed the data only for the combined weeks. A population-based series of 705 infants less than 26 weeks showed that antenatal corticosteroid treatment was associated with reductions in hospital mortality⁽²¹⁾, severe motor disability, and low mental developmental index⁽²²⁾. A study of 181 infants born at 23 weeks in 3 hospitals over a 10 year period reported reduction in mortality only in 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 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 mortality^(10,16,25) and severe disability^(13,26,27) in very preterm infants but have not focused the analysis on those born before 24 weeks. 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 was associated with lower rates of both mortality and important morbidities, including a lower rate of death/severe neurodevelopmental impairment at 18–22 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 viability⁽⁴⁾ 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. Antenatal corticosteroids may be considered starting at 23 weeks and later if the infant will be given intensive care, as this therapy is associated with reduced mortality and morbidity.

Supplementary Material

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Acknowledgments

Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

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.

Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Mr. Scott McDonald (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.

We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:

NRN Steering Committee Chair: Alan H. Jobe, MD PhD, University of Cincinnati; 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) – William Oh, MD; Betty R. Vohr, 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.

Brigham and Women’s Hospital, Children’s Hospital Boston, Beth Israel Deaconess Medical Center, and Harvard Medical School (U10 HD34167, M01 RR2635, M01 RR2172) – Ann R. Stark, MD; Kerri Fournier, RN; Stacy Dow, RN; Kimberly Gronsman Lee, MD; Colleen Driscoll.

Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80) – Deanne Wilson-Costello, MD; Bonnie S. Siner, RN.

Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084) – 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.

Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, M01 RR30) – 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.

Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39, UL1 RR25008) – David P. Carlton, MD; Lucky Jain, MD; Ira Adams-Chapman, MD.

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 (U10 HD53119, M01 RR54) – Elisabeth C. McGowan, MD; Brenda L. MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN BSN.

Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750, UL1 RR25761) – 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.

RTI International (U10 HD36790) – W. Kenneth Poole, PhD; Dennis Wallace, 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.

Stanford University, California Pacific Medical Center, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70, UL1 RR25744) – David K. Stevenson, MD; Susan R. Hintz, MD MS Epi; Marian M. Adams, MD; Alexis S. Davis, MD MS Epi; 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.

University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32) – 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.

University of California – San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461) – Neil N. Finer, MD; Maynard R. Rasmussen MD; 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.

University of Iowa Children’s Hospital (U10 HD53109, M01 RR59, UL1 RR24979) – John A. Widness, MD; Michael J. Acarregui, MD; Karen J. Johnson, RN BSN; Diane L. Eastman, RN CPNP MA.

University of Miami, Holtz Children’s Hospital (U10 HD21397) – 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.

University of New Mexico Health Sciences Center (U10 HD53089, M01 RR997) – Lu-Ann Papile, MD; Janell Fuller, MD; Jean Lowe, PhD; Conra Backstrom Lacy, RN; Rebecca Montman, BSN.

University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521, M01 RR44, UL1 RR24160) – 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.

University of Tennessee Health Science Center (U10 HD21415) – Sheldon B. Korones, MD; Henrietta S. Bada, MD; Marilyn G. Williams, LCSW; Kimberly Yolton, PhD.

University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – 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.

University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373) –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).

University of Utah University Hospital, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64, UL1 RR25764) – 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.

Wake Forest University Baptist Medical Center, Brenner Children’s Hospital, and Forsyth Medical Center (U10 HD40498, M01 RR7122) – T. Michael O’Shea, MD MPH; Robert Dillard, MD; Nancy J. Peters, RN CCRP; Barbara Jackson, RN BSN.

Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385) – 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.

Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, M01 RR125, M01 RR6022, UL1 RR24139) – 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.

Footnotes

Disclosures

In addition to the NIH grant support to the institutions identified in the Acknowledgements, the coauthors have the following potential conflicts of interest to report:

Waldemar A. Carlo, MD – Mednax, board member.

Dennis Wallace, PhD - NICHD & NIAID, funding from multiple NICHD and NIAID cooperative agreements in which RTI acts as the data center or statistical center for NIH-funded research activities; Mead Johnson, Travel expenses paid for statistical presentation for Neonatal Fellows at the Southeastern meeting in February 2010; Kansas University Medical Center Research Foundation, Royalties paid annually for work use of a Stroke Rehabilitation scale in clinical trials. Scale was developed while I was on the faculty at Kansas University Medical Center during the period of 1995 thru 2000; amount is less than $200 per year; NIDDK, NIDA, Johns Hopkins, serve on 3 DSMBs for research funded by NIDA, NIDDK/NIAID (Type I DM) and the Gates foundation. For annual meetings of these DSMBs, I receive a $200 honorarium for a 1-day meeting and coverage of flight and hotels to attend meeting.

Edward F. Bell, MD - CRED Foundation (www.cred.ro) Reimbursement of economy class airfare to attend annual conference of the Romanian Neonatology Association as a speaker; University of Alabama at Birmingham, Birmingham, AL, Travel, accommodations, and honorarium for 2 days as visiting professor; Children’s Mercy Hospital, Kansas City, MO, Travel and honorarium for participation as speaker at conference; Portuguese Neonatal Society, Travel and accommodations for speaking at annual meeting.

Pablo J. Sanchez, MD - Collaborative Antiviral Study Group; F. Hoffman-LaRoche, Ltd; Astellas; NIDCD.

Krisa P. Van Meurs, MD – Consulting/honorarium and equipment support from Ikaria; Travel, accommodations, and meeting expenses paid for by Actelion and Ikaria; Payment for expert testimony for various law suits from legal firms.

Roger G. Faix, MD – Ikaria Biosynexus, Fellow grant review committee for Ikaria Chair of DSMB for Biosynexus; Yale University subcontract, NINDS grant for Genes and IVH.

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