Lee, Henry C. MD, MS; Lyndon, Audrey RN, PhD; Blumenfeld, Yair J. MD; Dudley, R. Adams MD, MBA; Gould, Jeffrey B. MD, MPH
It has been known for more than 35 years that exposure to antenatal steroids decreases the incidence of neonatal respiratory distress syndrome and other morbidities in premature neonates.1,2 Therefore, it is the recommendation of obstetric and pediatric societies to routinely administer antenatal steroids to pregnant women when delivery is expected before 34 weeks of gestation.3–5 Nonetheless, only 75%–85% of eligible women receive antenatal steroids.6,7
A recent study of 790 neonates from a single region in France identified risk factors for not receiving antenatal steroids.6 These included medical factors, such as preterm birth associated with maternal bleeding, as well as sociodemographic factors, such as young maternal age. In their cohort of 790 premature neonates, 19.4% did not receive antenatal steroids.6 A similar population-based study has not been performed in the United States. Furthermore, the effect of sociodemographic factors may be different in a system with universal health care coverage and potential relevant factors in the United States, such as prenatal care and payment source, have yet to be investigated.6
Our objective was to estimate risk factors associated with lack of antenatal steroids administration in a contemporary data set. We also wanted to evaluate whether active participation in a quality-improvement collaborative, the California Perinatal Quality Care Collaborative, was associated with sustained improvement in care over time.
PATIENTS AND METHODS
The California Perinatal Quality Care Collaborative collects maternal and neonatal clinical data prospectively for neonates born at 128 member California hospitals using an expanded version of the Vermont Oxford Dataset.8,9 Membership is offered to any hospital in California that provides neonatal intensive care. In the study period from January 2005 to December 2007, more than 90% of California's neonatal intensive care admissions were cared for in California Perinatal Quality Care Collaborative hospitals. Clinical data from California Perinatal Quality Care Collaborative were linked to administrative data from the California Vital Records using a linkage strategy developed with the support of March of Dimes.10
The study population included 17,467 hospitalized newborns with a birth weight less than 1,500 g or gestational age less than 34 weeks born at a California Perinatal Quality Care Collaborative hospital during the study period. We excluded neonates whose antenatal steroid administration status was unknown (n=529) and neonates for whom linkage between California Perinatal Quality Care Collaborative and Vital Statistics could not be established (n=535). We also excluded neonates who died in the delivery room (n=1,041), because these neonates may have been born in circumstances in which there was a decision for nonresuscitation; therefore, antenatal steroids may not have been considered. Ninety percent of delivery room deaths occurred in neonates whose gestational age was 25 weeks or less. We further excluded neonates whose birth weight was larger than the 99th percentile for gestational age, based on previous norms, because these neonates were likely to have a miscoded gestational age (n=19).11 The number of participating hospitals that had eligible patients was 94 in 2005, 108 in 2006, and 113 in 2007.
We identified 15,343 eligible patients during the study period. We evaluated patient characteristics, including maternal demographics (age, race or ethnicity, prenatal care), obstetric conditions (fetal distress, diabetes, hypertension, bleeding, nonvertex presentation, premature rupture of membranes [rupture before delivery], prolonged rupture of membranes [defined as more than 18 hours of rupture], multiple gestations, mode of delivery), neonatal characteristics (sex, birth weight, gestational age at birth), birth year, and insurance status. Gestational age was the best estimate available, with the following hierarchy: 1) obstetric measures, based on last menstrual period, obstetrical parameters, or prenatal ultrasonography as recorded in the maternal chart and 2) neonatologist's estimate based on physical or neurologic examination, combined physical and gestational age examination (Ballard/Dubowitz), or examination of the lens. Data regarding the ultimate method used for estimating gestational age were not recorded.
We also evaluated the effect of previous quality-improvement activity, as determined by active group participation in a previous California Perinatal Quality Care Collaborative quality-improvement collaborative from 1999 to 2000 focused on improving antenatal steroids administration rates.7 The dissemination process for the collaborative was developed by the California Perinatal Quality Care Collaborative Perinatal Quality Improvement Panel using key components included in a quality-improvement tool kit made available to all members of the collaborative and webcasts and workshops that were open to all members but selectively attended. For our analysis, we considered those member hospitals that attended some or all of the webcasts and workshops as quality-improvement participants.
To assess the effect of level of neonatal care, we used the California Children's Services classification of neonatal intensive care units (NICUs) into three levels based on published guidelines by the American Academy of Pediatrics.12 Regional NICUs provide mechanical ventilation and major surgery without restriction (equivalent to American Academy of Pediatrics levels IIIC and IIID); community NICUs provide unrestricted care and ventilation to neonates of all gestational ages but are limited to surgery for only stable neonates or those with a patent ductus arteriosus (equivalent to American Academy of Pediatrics levels IIIA and IIIB); and intermediate NICUs provide care to a variably restricted population, ventilate only up to a specified number of hours, and refer all complicated cases to a higher level of care.12 There is a small number of hospitals in California that are not classified by California Children's Services.
The primary outcome of interest was antenatal steroids administration, defined as any dose of antenatal steroids administered before delivery. California Perinatal Quality Care Collaborative records antenatal steroids administration as a yes-or-no variable and does not record the exact timing of administration before time of birth.
We conducted univariable and multivariable analyses to examine associations with antenatal steroids administration. For univariable analyses, the Mann-Whitney test was used for continuous variables and χ2 test was used for categorical variables. For multivariable analysis, nonlinear mixed regression models were performed with PROC NLMIXED in SAS 9.2 (SAS Institute, Cary, NC), with individual hospitals modeled as a random effect. Forward stepwise selection was used to determine the optimal model. Mean antenatal steroids administration rates were compared between quality-improvement participants and nonparticipants, with both crude rates and after risk adjustment accounting for the significant factors determined from multivariable analysis. We derived antenatal steroids rates for each hospital as predicted random effects using mixed-effects logistic regression modeling that adjusted for significant variables from the stepwise selection. The strength of a random-effects model is to account for factors that are not determined even after risk adjustment for known risk factors and to allow attribution to being clustered at or cared for at a specific hospital. We fit the model using PROC NLMIXED, which calculates predicted random effects as posterior modes. Such predictions tend to “shrink” the crude rates; further descriptions of the relationship of predicted random effects and crude estimates are available elsewhere.13
The development of a strategy to link data from California Perinatal Quality Care Collaborative and California Vital Records was facilitated by a grant from the March of Dimes. This study was reviewed by the Institutional Review Boards of University of California San Francisco and Stanford University.
During 2005 to 2007, there were 15,343 eligible neonates born at California Perinatal Quality Care Collaborative hospitals, with an overall antenatal steroids administration rate of 76.9%. Neonates whose mothers received antenatal steroids were more likely to have had lower birth weight (1,220 compared with 1,350 g, P<.001) and to be delivered at an earlier gestational age (28.9 compared with 29.7 weeks, P<.001). Further characteristics of the study population and univariable analysis are shown in Table 1. In unadjusted analysis, neonates of mothers who were younger or Hispanic were less likely to receive antenatal steroids. Female neonates and those born from multiple gestations were more likely to receive antenatal steroids. Patients with private insurance had higher antenatal steroids rates (80.3%) compared with other payers (71.5%–73.7%, P<.001).
After 30 weeks of gestation, a mother was much less likely to receive antenatal steroids, with the antenatal steroids administration ranging from 80% to 85% from 24 to 30 weeks and then decreasing steadily from 78% at 31 weeks to 39% at 34 weeks of gestation (Fig. 1). Factors associated with not receiving antenatal steroids in multivariable analysis are shown in Table 2. Obstetrical conditions in which timing of delivery may have been a factor, such as fetal distress and vaginal delivery (compared with cesarean delivery), were associated with nonantenatal steroids administration when adjusting for maternal age, race or ethnicity, prenatal care, birth year, and NICU level. However, mothers who had rupture of membranes of any duration before delivery were more likely to receive antenatal steroids. Neonates with higher birth weights and those born at later gestational ages were less likely to receive antenatal steroids. Patients without prenatal care and those born at nonregional hospitals were also less likely to receive antenatal steroids.
Hospital rates of antenatal steroids administration varied widely (Fig. 2). During the years of the study, there were 11 hospitals that had participated in the previous California Perinatal Quality Care Collaborative quality-improvement project caring for 3,111 neonates. Forty-five percent of these were regional hospitals. The remaining 107 hospitals, 11% of which were regional hospitals, cared for 12,232 neonates. Neonates born at quality-improvement participant hospitals were more likely to receive antenatal steroids than those born at hospitals that did not participate, with unadjusted rate for quality-improvement participants being 85% compared with nonparticipants unadjusted rate of 69% (P<.001). After risk adjustment for risk factors identified in Table 2 and modeling individual hospital as a random effect, quality-improvement participants also had higher antenatal steroids administration rates than did nonparticipants (58% compared with 49%, P=.028). This method of modeling allowed for risk-adjusted comparison of hospitals, accounting for clustering at the hospital level and possibly resulting in shrunken estimates, which was consistent with the present analysis.
In this study of premature neonates born in California Perinatal Quality Care Collaborative hospitals, we found that contrary to well-established guidelines, 23.1% of mothers of neonates with birth weight less than 1,500 g or born at less than 34 weeks of gestation did not receive antenatal steroids. Moreover, this phenomenon was disproportionately evident among more vulnerable women (ie, no prenatal care, Hispanic women). Mothers giving birth after 30 weeks of gestation were less likely to receive antenatal steroids. Additionally, we found wide variation in the use of antenatal steroids among different hospitals, which was evident even after risk adjustment. We also found that participating in webcasts and workshops in a quality-improvement collaborative several years before the study period was associated with higher antenatal steroids administration.
Our findings are consistent with existing literature indicating 15%–25% of eligible neonates are not exposed to antenatal steroids and suggest specific targets for reducing inequalities in care.6,7 Through a new data linkage strategy, we were able to combine neonatal clinical data from California Perinatal Quality Care Collaborative with maternal clinical and sociodemographic data from California Vital Records. In unadjusted analyses, younger mothers were at higher risk for not receiving antenatal steroids, as has been described in other studies.6,14 There were also differences by race or ethnicity; however, after risk adjustment, the most prominent factors associated with not receiving antenatal steroids were neonatal level of care and lack of prenatal care (Table 2). Mothers in this higher-risk cohort may have greater benefit from antenatal steroids, considering that their neonates may be more vulnerable to being medically underserved or subject to disparities in access to care.
We also found that obstetrical conditions, such as vaginal birth, increased the likelihood of not receiving antenatal steroids. Although the lack of antenatal steroids in these cases may be related to the urgency of delivery, they still represent lost opportunities for improvement in quality of care. Although optimal neonatal benefit for antenatal steroids occurs after 24 hours of exposure before delivery, there is still likely to be some benefit if delivery occurs before this time.15,16 Furthermore, 10.1% of mothers with prolonged rupture of membranes (more than 18 hours) did not receive antenatal steroids. More than 80% of prolonged rupture of membranes was accounted for by neonates born before 32 weeks of gestation in this cohort. The American College of Obstetricians and Gynecologists recommends antenatal steroids for all neonates up to 32 weeks of gestation, even in the setting of premature membrane rupture, so lack of sufficient time could not have accounted for this finding in our cohort.3,28
In addition to sociodemographic and medical risk factors, we found that the rate of nonadministration of antenatal steroids increased rapidly in neonates being delivered between 30 and 34 weeks of gestation, with a sixfold increase in adjusted odds of not receiving antenatal steroids at 34 weeks of gestation. The reasons for this are unclear. This may represent a difference in the imminence of birth on maternal presentation at later gestational ages, or this may reflect reduced attention to the potential adverse consequences of moderately preterm birth. There has been recent interest in the increased risk of morbidity and mortality in late preterm neonates born between 34 and 37 weeks of gestation.18–21 The recognition that degree of prematurity presents something akin to a dose-dependent risk should also lead to closer attention of the moderately preterm neonates born from 30 to 34 weeks of gestation. These neonates are at even higher risk than late preterm neonates for respiratory and other morbidities, yet we found that the antenatal steroids rates in this population were markedly lower than those for neonates born at younger gestational ages.22 Given the evidence of benefit of antenatal steroids to 34 weeks and 6 days, there is opportunity to improve care for mothers with threatened preterm birth at these intermediate gestational ages.23–25
Risk-adjusted hospital-specific antenatal steroids rates for eligible neonates varied widely (Fig. 2), indicating substantial variation that cannot be explained by hospital characteristics. Considering that there remained large hospital variation in practice after risk adjustment suggests that there are substantial opportunities for improving antenatal steroids rates at many facilities.
The evidence that antenatal steroids administration reduces the risk of neonatal death, respiratory distress syndrome, and other morbidities in premature neonates has led to it being the standard of care for at least the past decade.3–5,16,23 Because of the evidence supporting its use, antenatal steroids administration increased dramatically in the 1990s from 23.8% in 1991 to 71.6% in 1999 in the Vermont Oxford Network.26 Although the causes of this increase have not been studied in detail, directed quality-improvement interventions have been used successfully to increase antenatal steroids rates.7,27,28
One such effort occurred within the California Perinatal Quality Care Collaborative from 1999 to 2000. Details of the dissemination strategy have been described previously.7 An antenatal steroids tool kit was developed and disseminated. A series of interactive workshops and webcasts were then provided. Although the tool kit was available to all California Perinatal Quality Care Collaborative members, not all hospitals participated in the workshops. Antenatal steroids rates increased from 76% in 1998 to 86% in 2001.7
The sustainability of quality-improvement initiatives is an increasing area of scrutiny. There has been a dearth of studies on long-term effects of quality-improvement collaborative efforts and, specifically, none has examined the sustainability of efforts to improve antenatal steroids administration.29 For our analysis, we considered those hospitals that sent representatives to participate in the workshops and webcasts as quality intervention participants. We found that the efforts of this group were associated with long-term change; participating hospitals had higher rates of antenatal steroids administration than other hospitals 5 to 7 years after the end of the intervention. Furthermore, there was evidence of holding the gains of the previous collaborative, with antenatal steroids rates in the quality-improvement participants remaining at 85%.
Limitations of our study include those related to the obstetrical data collected. Antenatal steroids administration is categorized by the California Perinatal Quality Care Collaborative as any dose of antenatal steroids administered before delivery as opposed to a complete course. Therefore, our reported rate of antenatal steroids administration likely overestimates the rate of the more optimal complete antenatal steroids course. We were unable to determine if some mothers may have been admitted to the hospital just before delivery, without enough time for antenatal steroids administration. Finally, the comparison of antenatal steroids rates by quality-improvement collaborative participation was not the result of a randomized controlled design. There may be some degree of selection bias in that hospitals that participated may have other factors relevant to their success. Nevertheless, the higher antenatal steroids administration rates in quality-improvement participants are encouraging, because they suggest that the collaborative effort was associated with a sustained improvement at those hospitals. As quality improvement becomes a higher priority in medicine, further research should focus on not only the effectiveness of quality improvement but also its sustainability.
We found that there is still a concerning proportion of eligible patients at risk for not receiving antenatal steroids. It may be that relatively “easy” cases to identify and treat, such as those followed-up through prenatal care with identification of being high risk conditions, are generally being treated appropriately. However, mothers who present without prenatal care or mothers who present suddenly without warning, with imminent delivery (or both) may be at highest risk for not receiving antenatal steroids. There also may be some complacency toward antenatal steroids administration at later, yet still eligible, gestational ages. Quality-improvement initiatives to target such mothers may be the next priority in further efforts to increase antenatal steroids rates. Our study showed that a collaborative effort by California Perinatal Quality Care Collaborative may have had a lasting effect on participating hospitals, which is an encouraging result in this era of quality improvement.
1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.
2. Crowley P. Prophylactic corticosteroids for preterm birth. The Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD000065.
3. Antenatal corticosteroid therapy for fetal maturation. ACOG Committee Opinion No. 402. American College of Obstetricians and Gynecologists. Obstet Gynecol 2008;111:805–7.
4. Antenatal corticosteroid therapy for fetal maturation. ACOG Committee Opinion No. 210. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1999;64:334–5.
5. Miracle X, Di Renzo GC, Stark A, Fanaroff A, Carbonell-Estrany X, Saling E, et al. Guideline for the use of antenatal corticosteroids for fetal maturation. J Perinat Med 2008;36:191–6.
6. Burguet A, Ferdynus C, Thiriez G, Bouthet MF, Kayemba-Kays S, Sanyas P, et al. Very preterm birth: who has access to antenatal corticosteroid therapy? Paediatr Perinat Epidemiol 2010;24:63–74.
7. Wirtschafter DD, Danielsen BH, Main EK, Korst LM, Gregory KD, Wertz A, et al. Promoting antenatal steroid use for fetal maturation: results from the California Perinatal Quality Care Collaborative. J Pediatr 2006;148:606–12.
9. California Perinatal Quality Care Collaborative Network Database 2008 Member Instructions for Electronic Data Submission. Version 01.08. Available at: http://www.cpqcc.org
11. Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr 2003;3:6.
12. Stark AR. Levels of neonatal care. Pediatrics 2004;114:1341–7.
13. McCulloch CE, Searle SR, Neuhaus JM. Prediction. Generalized, linear, and mixed models. 2nd ed. Hoboken (NJ): Wiley-Interscience; 2008. P. 303–19.
14. Foix-L'Helias L, Marret S, Ancel PY, Marchand L, Arnaud C, Fresson J, et al. Impact of the use of antenatal corticosteroids on mortality, cerebral lesions and 5-year neurodevelopmental outcomes of very preterm infants: the EPIPAGE cohort study. BJOG. 2008;115:275–82.
15. Gates S, Brocklehurst P. Decline in effectiveness of antenatal corticosteroids with time to birth: real or artefact? BMJ 2007;335:77–9.
16. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:11–25.
17. Premature rupture of membranes. ACOG Practice Bulletin No. 80. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:1007–19.
18. Jain L. Morbidity and mortality in late-preterm infants: more than just transient tachypnea! J Pediatr 2007;151:445–6.
19. Chyi LJ, Lee HC, Hintz SR, Gould JB, Sutcliffe TL. School outcomes of late preterm infants: special needs and challenges for infants born at 32 to 36 weeks gestation. J Pediatr 2008;153:25–31.
20. McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol 2008;111:35–41.
21. Raju TN. Epidemiology of late preterm (near-term) births. Clin Perinatol 2006;33:751–63, abstract vii.
22. Marret S, Ancel PY, Marpeau L, Marchand L, Pierrat V, Larroque B, et al. Neonatal and 5-year outcomes after birth at 30–34 weeks of gestation. Obstet Gynecol 2007;110:72–80.
23. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454.
24. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks' gestational age. Pediatrics 2010;126:115–28.
25. Joseph KS, Nette F, Scott H, Vincer MJ. Prenatal corticosteroid prophylaxis for women delivering at late preterm gestation. Pediatrics 2009;124:e835–43.
26. Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, et al. Trends in mortality and morbidity for very low birth weight infants, 1991–1999. Pediatrics 2002;110(1 Pt 1):143–51.
27. Leviton LC, Goldenberg RL, Baker CS, Schwartz RM, Freda MC, Fish LJ, et al. Methods to encourage the use of antenatal corticosteroid therapy for fetal maturation: a randomized controlled trial. JAMA 1999;281:46–52.
28. Horbar JD, Carpenter JH, Buzas J, Soll RF, Suresh G, Bracken MB, et al. Collaborative quality improvement to promote evidence based surfactant for preterm infants: a cluster randomised trial. BMJ 2004;329:1004.
29. Schouten LM, Hulscher ME, van Everdingen JJ, Huijsman R, Grol RP. Evidence for the impact of quality improvement collaboratives: systematic review. BMJ 2008;336:1491–4.