Obstetrics & Gynecology:
Variations in Antenatal Corticosteroid Therapy: A Persistent Problem Despite 30 Years of Evidence
Chien, Li‐Yin MPH, ScD; Ohlsson, Arne MD, MSc; Seshia, Mary M. K. MBChB, FRCP(Ed); Boulton, Jill MD, FRCPC; Sankaran, Koravangattu MBBS, FRCPC; Lee, Shoo K. MBBS, FRCPC; for The Canadian Neonatal Network
Institute of Community Health Nursing, School of Nursing, National Yang‐Ming University, Taipei, Taiwan; Department of Pediatrics, University of Toronto, Toronto, Ontario; Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba; Department of Pediatrics, University of Western Ontario, London, Ontario; Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia; and Centre for Community Health and Health Evaluation Research, Vancouver, British Columbia, Canada.
Address reprint requests to: Shoo K. Lee, MBBS, FRCPC, PhD, Canadian Neonatal Network Coordinating Centre, 4480 Oak Street, Rm E‐414, Vancouver, British Columbia V6H 3V4, Canada; E‐mail: email@example.com.
Members of the Canadian Neonatal Network: Shoo K. Lee, MBBS, FRCPC, PhD (Coordinator, Canadian Neonatal Network, Centre for Community Health and Health Evaluation Research, Vancouver, BC); Wayne Andrews, MD, FRCPC (Charles A. Janeway Child Health Centre, St. John's, NF); Ranjit Baboolal, MBChB, FRCPC (North York Hospital, N. York, ON); Jill Boulton, MD, FRCPC (St. Joseph's Health Centre, London, ON; formerly at Mt. Sinai Hospital, Toronto, ON); David Brabyn, MBChB, FRACP, FRCPC (Royal Columbian Hospital, New Westminster, BC); David S. C. Lee, MBBS, FRCPC (St. Joseph's Health Centre, London, ON); Derek Matthew, MRCS, FRCPC, SM (Victoria General Hospital, Victoria, BC); Douglas D. McMillan, MD, FRCPC (Foothill's Hospital, Calgary, AB); Christine Newman, MD, FRCPC (Hospital for Sick Children, Toronto, ON); Arne Ohlsson, MD, FRCPC, MSc (Mt. Sinai Hospital, Toronto, ON; formerly at Women's College Hospital, Toronto, ON); Abraham Peliowski, MD, FRCPC (Royal Alexandra Hospital, Edmonton, AB); Margaret Pendray, MBBS, FRCPC (Children's and Women's Health Centre of British Columbia, Vancouver, BC); Koravangattu Sankaran, MBBS, FRCPC (Royal University Hospital, Saskatoon, SK); Barbara Schmidt, MD, FRCPC, MSc (McMaster University Medical Centre, Hamilton, ON); Mary M. K. Seshia, MBChB, FRCP(Ed), FRCPCH (Health Sciences Centre, Winnipeg, MB); Anne Synnes, MDCM, FRCPC, MHSc (Children's and Women's Health Centre of British Columbia, Vancouver, BC; formerly at Montreal Children's Hospital, Montreal, PQ); Paul Thiessen, MD, FRCPC (Children's and Women's Health Centre of British Columbia, Vancouver, BC); Robin Walker, MD, FRCPC (Children's Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, ON); and Robin Whyte, MBBS, FRCPC (IWK‐Grace Health Centre for Women, Children and Families, Halifax, NS). Members of the Canadian Neonatal Network Coordinating Centre (Vancouver, BC): Li‐Yin Chien, MPH, ScD, Joanna Sale, MSc, Herbert Chan, MSc, and Shawn Stewart, BA.
This study was supported by Grant 40503 and Grant 00152 from the Medical Research Council of Canada.
Received June 11, 2001. Received in revised form October 23, 2001. Accepted November 1, 2001.
OBJECTIVE: To document current use of antenatal corticosteroid therapy in a large cohort of Canadian preterm infants admitted to neonatal intensive care units, and to assess the impact of variations in use on neonatal outcomes.
METHODS: The study subjects included 11,440 infants less than 38 weeks' gestation who were admitted to 17 Canadian Neonatal Network intensive care units from January 1996 to October 1997. Data analyses were conducted separately for infants less than 24 weeks' gestation, 24–34 weeks' gestation, and over 34 weeks' gestation. Logistic regression analysis was used to model the examined relationships, controlling for patient characteristics.
RESULTS: The incidence of antenatal corticosteroid treatment was 42% for infants less than 24 weeks' gestation, 59% for infants 24–34 weeks' gestation, and 10% for infants over 34 weeks' gestation. Antenatal corticosteroid treatment was associated with reduced risk for neonatal mortality and respiratory distress syndrome, but not for infants over 34 weeks' gestation. Significant institutional variations in antenatal corticosteroid use were present among both inborn and outborn infants. Increased antenatal corticosteroid treatment for infants 24–34 weeks' gestation can potentially reduce the number of neonatal deaths by 41 cases (10%) and respiratory distress syndrome by 90 cases (3%) among participating hospitals.
CONCLUSION: Wide institutional differences persist in the incidence of antenatal corticosteroid treatment for women expected to give birth preterm. Increased use of antenatal corticosteroids for preterm deliveries can reduce neonatal mortality in Canada by up to 10%.
In 1972, Liggins and Howie first reported that antenatal corticosteroid treatment of women expected to give birth preterm significantly reduced the incidence of respiratory distress syndrome (RDS) and mortality among neonates.1 These findings have since been replicated in numerous randomized trials and observational studies. In a meta‐analysis of 18 placebo‐controlled randomized trials from 1972 to 1995, Crowley showed that antenatal corticosteroid therapy reduced the odds ratio (OR) of neonatal RDS by 47% and of neonatal mortality by 40% among infants born preterm, and attenuated the OR of intraventricular hemorrhage by 52%.2 Despite the abundance of evidence, antenatal corticosteroid treatment of women at risk of preterm birth has not been fully accepted and widely used by medical care providers. Indeed, 13 international trials of surfactant use in preterm infants published between 1989 and 1994 showed infrequent and variable antenatal corticosteroid use (mean 12%; range 0.8–81%).3 In 1993, the Vermont Oxford Network reported that only 34.1% (median institutional use 25%) of very low birth weight infants admitted to their neonatal intensive care units (NICUs) received antenatal corticosteroid treatment.4 Concerns about the uneven use of antenatal corticosteroid treatment led the United States National Institutes of Health to convene a Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation and Perinatal Outcomes in 1994. The Consensus Conference Statement recommending antenatal corticosteroid therapy for women at risk of preterm birth between 24 and 34 weeks' gestation was adopted by the Society of Obstetricians and Gynaecologists of Canada as clinical practice guidelines in 1995, and it was anticipated that this would lead to increased use of antenatal corticosteroids with decreased variation in use among institutions.5
The objectives of this study were to document current use of antenatal corticosteroid therapy in a large Canadian cohort of preterm infants admitted to 17 NICUs of the Canadian Neonatal Network in 1996–1997, and to assess the impact of variations in use on neonatal outcomes.
MATERIALS AND METHODS
The study population included 11,440 infants less than 38 weeks' gestation admitted to NICUs in the Canadian Neonatal Network during a 22‐month period from January 1996 to October 1997.6 The Canadian Neonatal Network includes 17 NICUs throughout Canada, representing 75% of all tertiary level NICU beds in Canada, and serving a population of about 22 million people. All but one are regional tertiary referral centers. Each NICU serves a distinct geographic region and coordinates infant transfer within the region through a regional infant transport system. Outborn admissions comprised 28% (interinstitutional range 4–100%) of admissions to the NICUs. Three NICUs admitted only outborn infants. Of the 11,440 infants in the study cohort, 122 (1%) were less than 24 weeks' gestation, 7616 (67%) were between 24 and 34 weeks' gestation, and 3702 (32%) were between 35 and 37 weeks' gestation.
Study variables were defined according to the Canadian Neonatal Network Data Abstractor Manual. Antenatal corticosteroid treatment was coded as none if no corticosteroid was administered to the infant's mother at anytime before the delivery, as partial if the infant was delivered less than 24 hours after the mother received her first dose or more than 1 week after she received her last dose, and as complete if the infant was delivered more than 24 hours and less than 1 week after the mother received a dose of corticosteroids. The category of any corticosteroids included infants in either the partial or complete groups. An infant was defined as small for gestational age (SGA) if the birth weight was less than the 3rd percentile for gestational age according to the British Columbia provincial growth charts (Whitfield M. British Columbia provincial growth chart. Vancouver: British Columbia Children's Hospital; 1992). Prenatal care was defined as receipt of pregnancy‐related care from a physician on at least one occasion (not related to a visit for diagnosis of pregnancy) during pregnancy. Chronic lung disease was defined as oxygen dependency at 36 weeks' corrected gestational age for an infant who was born at less than 33 weeks' gestation.7 Intraventricular hemorrhage was defined according to the criteria of Papile et al from head ultrasound performed before 14 days of life.8 Necrotizing enterocolitis was defined according to the criteria of Bell et al.9 Retinopathy of prematurity was defined according to the International Classification for Retinopathy of Prematurity10 and the Reese et al classification of cicatrical disease.11 Infection was defined using blood and cerebrospinal fluid culture results according to the criteria of Freeman et al.12 Infection was classified as primary if bacteria were noted in a blood culture obtained at less than 48 hours' postnatal age, and nosocomial if a pure positive culture was reported at any time beyond 48 hours' postnatal age. Patent ductus arteriosus was defined as clinical diagnosis plus treatment with indomethacin or surgical ligation or both. Respiratory distress syndrome was defined by typical clinical symptoms such as grunting and retractions, and/or a chest x‐ray compatible with RDS or treatment with surfactant.
The data were analyzed separately for infants less than 24 weeks' gestation, 24–34 weeks' gestation, and over 34 weeks' gestation. One‐variable and two‐variable analyses were used to describe patient characteristics and to identify risk factors correlated with neonatal mortality and morbidity (including chronic lung disease, intraventricular hemorrhage, primary infection, nosocomial infection, patent ductus arteriosus, necrotizing enterocolitis, RDS, and retinopathy of prematurity). Multivariable logistic regression analyses were used to examine the factors associated with antenatal corticosteroid use, and the relationship between antenatal corticosteroid treatment and neonatal mortality and morbidity, adjusting for baseline patient risk factors (including sex, SGA, gestational age, maternal hypertension, multiple gestations, prenatal care, cesarean delivery, inborn or outborn status) and surfactant use. We estimated the number of deaths and adverse neonatal outcomes that could be avoided if all NICUs achieved the highest incidence of observed antenatal corticosteroid use in a NICU for infants 24–34 weeks' gestation. The expected number of infants with adverse outcomes for the cohort was calculated from the respective logistic regression models using the highest observed rate of antenatal corticosteroid use in a NICU. The excess number of infants with adverse outcomes was obtained by subtracting the expected from the observed number of infants with adverse outcomes. Statistical analyses were performed using the SPSS for Windows software 9.0 (SPSS Inc., Chicago, IL).
Figure 1 shows the incidence of partial and complete antenatal corticosteroid treatment among infants admitted to a NICU by gestational age. The overall incidence was 42% for infants less than 24 weeks' gestation (partial 22%, complete 20%), 59% for infants 24–34 weeks' gestation (partial 27%, complete 32%), and 10% for infants over 34 weeks' gestation (partial 6%, complete 4%). The incidence was highest among infants born at 25–31 weeks' gestation (mean incidence 72%, with 32% partial and 40% complete), and decreased with lower and higher gestational age.
Maternal and infant characteristics of the study subjects are presented in Table 1. Infants who had received antenatal corticosteroid treatment were less mature, more likely to be SGA, and less likely to be delivered outside perinatal centers. Table 2 shows the factors associated with lack of antenatal corticosteroid use for infants over 24 weeks' gestation. For infants less than 24 weeks' gestation, patient characteristics were not associated with lack of antenatal corticosteroid use, but this could be attributed to the small numbers of patients. For infants 24–34 weeks' gestation, factors associated with lack of antenatal corticosteroid treatment were gestational age less than 25 weeks or over 31 weeks, singleton gestation, lack of prenatal care, and outborn status. For infants over 34 weeks' gestation, factors associated with lower antenatal corticosteroid use were higher gestational age, not SGA, vaginal delivery, singleton gestation, and outborn status.
Table 3 shows that antenatal corticosteroid therapy had different effects on neonatal mortality and morbidity among infants of different gestational age in the NICU. After adjustment for baseline population risks and surfactant treatment, complete but not partial antenatal corticosteroid treatment was associated with decreased risk of death (OR 0.23, 95% confidence interval [CI] 0.07, 0.75) and RDS (OR 0.08, 95% CI 0.01, 0.99) for infants less than 24 weeks' gestation. Any or partial antenatal corticosteroid treatment was associated with increased risk of subsequent nosocomial infection (any: OR 3.43, 95% CI 1.01, 11.67; partial: OR 4.27, 95% CI 1.09, 16.74). For infants 24–34 weeks' gestation, any use of antenatal corticosteroid treatment decreased the risk of death (OR 0.74, 95% CI 0.59, 0.94) and RDS (OR 0.85, 95% CI 0.74, 0.97), but increased the subsequent risk for nosocomial infection (OR 1.28, 95% CI 1.08, 1.53). Isolated effects of partial but not complete antenatal corticosteroid treatment on the incidence of chronic lung disease, intraventricular hemorrhage, and retinopathy of prematurity may indicate that partial treatment is a proxy for other risks. Antenatal corticosteroid therapy did not affect outcomes of infants born after 34 weeks' gestation. The effect of antenatal corticosteroid therapy was independent of surfactant use for infants born at 24–34 weeks' gestation. Exclusion of surfactant use from the model further reduced the OR of death and RDS with any antenatal steroid treatment to 0.65 (95% CI 0.52, 0.82) and 0.80 (95% CI 0.71, 0.89), respectively.
Figure 2 shows the incidence of partial and complete antenatal corticosteroid treatment among inborn infants admitted to 14 of the 17 NICUs (three NICUs admitted only outborn infants), stratified by gestational age groups. The incidence was higher among inborn (median 48.3%, range 18.4–91.3%) than outborn (median 20.1%, range 6.2–88.9%) infants for all gestational age groups. There were wide variations in the incidence of antenatal corticosteroid treatment among neonates admitted to the 17 institutions for all gestational age groups. The variations were larger among outborn than inborn infants, especially for infants 24–34 weeks' gestation (outborn incidence range 7.9–94.1%; inborn incidence range 24.5–96.2%). The variations were larger at the extremes of gestational age (less than 24 weeks and over 34 weeks).
For infants 24–34 weeks' gestation, the highest incidence of antenatal corticosteroid use achieved by an individual institution was 94%. Assuming that this incidence is achievable by all institutions, increased antenatal corticosteroid treatment will result in an annual reduction in the number of neonatal deaths by 41 cases (10% of all neonatal deaths) and RDS by 90 cases (3%), but an increase of 44 cases (5%) of nosocomial infection will occur.
Our finding of significant variation in antenatal corticosteroid use among Canadian perinatal centers is consistent with reports in the early 1990s.13,14 Although we found that variations were larger among community hospitals (outborn infants), they were also prevalent among tertiary level academic institutions (inborn infants). These findings highlight the difficulties associated with translating evidence and consensus practice guidelines into clinical practice. Leviton et al reported that factors associated with low incidence of antenatal corticosteroid use included skepticism about the benefit, fear of infection, and uncertainty about the timing of corticosteroid administration.15 Erickson et al reported that physician characteristics, including physicians' residency training, age, and knowledge, were associated with use of antenatal corticosteroids.16 Cabana et al suggested that other reasons for lack of adherence to practice guidelines included lack of self‐confidence, inertia of previous practice, and external and environmental factors.17 We found that outborn status and lack of prenatal care were also associated with low incidence of antenatal corticosteroid therapy. Although sudden unexpected events may preclude treatment with antenatal corticosteroids, it is also possible that improved prenatal care and better community health care provider awareness and compliance with consensus practice guidelines may increase the incidence of treatment with antenatal corticosteroids.
The excess burden of illness arising from variation in the incidence of antenatal corticosteroid use is significant. We estimated that if all institutions achieved the highest incidence of antenatal corticosteroid use reported by a participating institution, the incidence of mortality and RDS among participating NICUs could be reduced by 10% and 3%, respectively. Innovative ways to better motivate change in clinical practice must be developed and implemented. Wennberg et al reported that feedback of data to institutions that deviate from the norm can motivate change in clinical practice.18 Leviton et al reported that active, focused efforts increased the effectiveness of guideline dissemination.19 Programs using similar strategies should be used to encourage increased use of antenatal corticosteroids and should focus especially on physicians in community practice. For example, physician order sheets could have printed prompts for antenatal corticosteroid treatment, in‐hospital surveillance systems could notify physicians about untreated patients in real time, clinician leaders can target specific groups of low‐usage providers for communication and continuing medical education, and clinical aids such as the Maternity Care Calendar Wheel can be used to alert clinicians and mothers to the need for prenatal interventions by outlining important clinical information, eg, optimal timing for recommended prenatal activities, amniocentesis, maternal serum screening, and ultrasounds (Institute for Clinical Evaluative Sciences. Maternity care calendar: A new spin on the old wheel. Informed 6:2. Toronto, Canada: Institute for Clinical Evaluative Sciences, 2000). Implementation of a national system of ongoing audit and feedback to clinicians at both academic and community hospitals and a broad effort to provide focused education about the benefits and risks of antenatal corticosteroid therapy can have a significant impact on neonatal mortality, morbidity, and health care resource use.
Despite these concerns, 59% of infants born at 24–34 weeks' gestation in our study cohort received antenatal corticosteroids compared with 32–35% in multicenter trials of treatment for preterm labor in the early 1990s.13,14 These results suggest a trend of increasing antenatal corticosteroid use over time. Similar trends were reported by Wright et al in the United States after publication of the National Institutes of Health Consensus Conference Statement in 1994 (Wright L, Merenstein G, Goldenberg RL, Clever SP, Rowe M. Impact of the National Institutes of Health Consensus Development Conference on corticosteroids for fetal maturation: Changes in obstetric attitudes [abstract]. Pediatr Res 1996;39:254A). The lower incidence of antenatal corticosteroid use among infants less than 24 weeks' gestation may be related to questions about the appropriateness of aggressive treatment for infants at the margins of viability, feasibility of administering corticosteroids to women in imminent labor, and long‐term outcomes of treatment. Our finding that antenatal corticosteroid treatment did not benefit infants over 35 weeks' gestation suggests that at least some patients may have been treated unnecessarily. Benediktsson et al further suggest that in utero exposure to antenatal corticosteroids may induce lifelong hypertension.20 Because there is significant mortality and morbidity among infants under 35 weeks' gestation, most clinicians will agree that the risk‐benefit ratio for using antenatal corticosteroids is favorable. However, for infants over 34 weeks' gestation, it may be prudent to limit antenatal corticosteroid treatment to those with proven lung immaturity.21 Our results confirm previous findings that antenatal corticosteroid therapy reduces neonatal mortality and RDS.2,13 Unlike Crowley, we did not find an independent effect of antenatal corticosteroid therapy on the incidence of intraventricular hemorrhage.2 Crowley's meta‐analysis of four studies on intraventricular hemorrhage included Morales et al's report,22 which used a quasirandom method of patient allocation. Strict enforcement of the inclusion criteria of true randomization would have excluded this study and may have altered the results of the meta‐analysis. There is conflicting evidence in the literature about whether antenatal corticosteroids increase the risk of neonatal infection. Ohlsson reported that antenatal corticosteroid use increased the incidence of endometritis, and there was a trend toward an increase in neonatal infections when there was premature rupture of membranes (PROM).23 More recently, a meta‐analysis showed that antenatal corticosteroid use among mothers with PROM did not increase the risk of neonatal infections.24 Vermillion et al found that treatment with multiple, but not single courses of antenatal corticosteroids increased the risk of neonatal infections among mothers with PROM.25 Like Gunkel and Mitchell, we found an association between antenatal corticosteroid treatment and neonatal infections, but this was not confirmed in Crowley's meta‐analysis of 15 randomized controlled trials.26,2
Finally, because our study is observational in nature, it is important not to overinterpret the observed associations. It is also possible that increased survival with prolonged duration of NICU stay or unobserved obstetric and maternal factors (eg, maternal illness, fetal distress, chorioamnionitis, tocolysis, PROM, and other perinatal treatments) may affect the associations,27,28 and more complete analyses of these factors are required.
1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.
2. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 3. Oxford, UK: Update Software, 2001.
3. Ryan CA, Finer NN. Antenatal corticosteroid therapy to prevent respiratory distress syndrome. J Pediatr 1995;126:317–9.
4. Horbar JD. Increasing use of antenatal corticosteroid therapy between 1990 and 1993 in Vermont Oxford Network. J Perinatol 1997;17:309–13.
5. National Institute of Child Health and Human Development Office of Medical Applications Research, NIH. Effect of corticosteroids for fetal maturation on perinatal outcomes, publication 95-3784. Bethesda, MD: National Institutes of Health, 1994.
6. Lee SK, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R, et al. Variations in practice and outcomes in the Canadian NICU Network: 1996–1997. Pediatrics 2000; 106:1070–9.
7. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in preterm infants: Prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527–32.
8. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 g. J Pediatr 1978;92:529–34.
9. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based on clinical staging. Ann Surg 1987; 187:1–7.
10. International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Pediatrics 1984;74:127–33.
11. Reese AB, King MJ, Owens WC. A classification of retrolental fibroplasia. Am J Ophthalmol 1953;36:1333.
12. Freeman J, Epstein MF, Smith NE, Platt R, Sidebottom DG, Goldman DA. Extra hospital stay and antibiotic usage with nosocomial coagulase negative staphylococcal bacteremia in two neonatal intensive care unit populations. Am J Dis Child 1990;144:324–9.
13. Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respiratory distress syndrome: Discussion. Am J Obstet Gynecol 1995;173:335–44.
14. Dunn MS, Shennan AT, Possmayer F. Single-versus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome. Pediatrics 1990;86:564–71.
15. Leviton LC, Baker S, Hassol A, Goldenberg RL. An exploration of opinion and practice patterns affecting low use of antenatal corticosteroids. Am J Obstet Gynecol 1995;173:312–6.
16. Erickson K, Schmidt L, Santesso DL, Schulkin J, Gregory K, Hobel C. Obstetrician-gynecologists' knowledge and training about antenatal corticosteroids. Obstet Gynecol 2001;97:140–6.
17. Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud PAC, et al. Why don't physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999;282:1458–65.
18. Wennberg JE, Blowers L, Parker R, Gittelsohn AM. Changes in tonsillectomy rates associated with feedback and review. Pediatrics 1977;59:821–6.
19. 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. JAMA 1999;281:46–52.
20. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CRW. Glucocorticoid exposure in utero: New model for adult hypertension. Lancet 1993;341:339–41.
21. Wallace EM, Chapman J, Stenson B, Wright S. Antenatal corticosteroid prescribing: Setting standards of care. Br J Obstet Gynaecol 1997;104:1262–6.
22. Morales WJ, Diebel ND, Lazar AJ, Zadrozny D. The effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome in preterm gestations with premature rupture of membranes. Am J Obstet Gynecol 1986;154:591–5.
23. Ohlsson A. Treatments of preterm premature rupture of the membranes: A meta analysis. Am J Obstet Gynecol 1989;160:890–906.
24. Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol 2001;184:131–9.
25. Vermillion ST, Soper DE, Chasedunn-Roark J. Neonatal sepsis after betamethasone administration to patients with preterm premature rupture of membranes. Am J Obstet Gynecol 1999;181:320–7.
26. Gunkel JH, Mitchell BR. Observational evidence for the efficacy of antenatal steroids from randomized studies of surfactant replacement. Am J Obstet Gynecol 1995;173:281–5.
27. Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR, et al. Late onset sepsis in very low birth weight neonates: A report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:63–71.
28. Horbar JD, for the investigators of the Vermont-Oxford Trials Network. Antenatal corticosteroid treatment and neonatal outcomes for infants 501 to 1500 grams in the Vermont-Oxford Trials Network. Am J Obstet Gynecol 1995;173:275–81.
© 2002 The American College of Obstetricians and Gynecologists
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