Review articles

By Ms. Farah Saeed , Mr. Muhammed R Siddiqui
Corresponding Author Ms. Farah Saeed
University of Liverpool, - United Kingdom
Submitting Author Mr. Muhammed R Siddiqui
Other Authors Mr. Muhammed R Siddiqui
Mayday Hospital, 23 Malvern Road - United Kingdom TN24 8HX


Antenatal Steroids, Respiratory Distress, Neonatology

Saeed F, Siddiqui MR. A Literature Review on Multiple Courses of Antenatal Steroids to Prevent Neonatal Respiratory Distress Syndrome. WebmedCentral OBSTETRICS AND GYNAECOLOGY 2011;2(4):WMC001842
doi: 10.9754/journal.wmc.2011.001842
Submitted on: 03 Apr 2011 07:01:41 PM GMT
Published on: 05 Apr 2011 04:43:16 PM GMT


Introduction: Repeat antenatal corticosteroids may reduce respiratory distress syndrome however there is conflicting evidence suggesting it may be unnecessary or harmful. This article reviews the literature to examine the role of multiple courses of antenatal steroids to prevent neonatal respiratory distress syndrome.
Methods: Electronic databases were searched online.
Results: Four randomised controlled trials were identified according to our inclusion criteria. Conclusions: There is evidence that courses of ACS improve pulmonary outcomes in the neonate, preventing RDS. There is evidence suggesting potential harm, and the lack of long term safety data, caution and careful patient selection is required when instituting this intervention.


There are approximately 500,000 preterm deaths per year worldwide1 and is a significant proportion of neonatal mortality. Premature infants are at a high risk of medical complications such as intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), patent ductus arteriosus (PDA), retinopathy of prematurity (ROP) and sepsis. However the main cause of early death in premature infants is still respiratory distress syndrome (RDS)2.
RDS often occurs in babies born before 32 weeks of gestation; the risk depends on earlier birth. Endogenous corticosteroids interact with other hormones in the foetus to control tissue maturation. Babies born preterm have immature lungs and an insufficient amount of surfactant in the lungs which may cause RDS3. The most important and most effective known prevention of RDS in preterm infants is a course of antenatal corticosteroids (ACS) given to the mother4.
ACS speeds up foetal lung development by mimicking the effect of endogenous corticosteroids5. This is achieved by inducing surfactant components and important lipogenic enzymes and stimulating pneumonocytes that normally appear in the foetal lung at about 24-28 weeks gestation3. The production of endogenous surfactant is increased and improves lung compliance, thereby reducing the incidence of RDS. A relatively brief exposure of a foetus to corticosteroids may accelerate the normal developmental process in the lung and other tissues.
The discovery that ACS treatment improves foetal maturation and decreases the risk of RDS was made by Professor Liggins about four decades ago. While working on research on labour initiation, Liggins noticed that preterm lambs exposed to corticosteroids in the womb were “viable at an earlier gestational age, had less severe respiratory distress, and had structurally more mature lungs than would be anticipated”6. This observation was then confirmed in humans in 1972 in a controlled trial where incidence of RDS was significantly reduced (4.3% vs 24%) in infants under 37 weeks gestation after corticosteroid treatment7. This finding has been supported by other investigators8.
The scientific basis for this relationship between lung maturation, steroids, and RDS is convincing. For example, glucocorticoids administered to foetal rabbits stimulated development of many types of lung cells, including type II alveolar cell9 which is the site of surfactant synthesis. Many other studies in animal species have confirmed this, and experiments have shown organ maturation is delayed when there is a deficiency of endogenous corticosteroid. It is thus that administering repeat courses of corticosteroids to mothers at risk of preterm birth became commonplace, despite a paucity of data confirming safety and efficacy of additional exposures of ACS.
Current UK practice
Most obstetric units in the UK administer two doses of betamethasone or dexamethasone over 24 hours as a single course10. However the time between administration of steroids and delivery alters their effectiveness, and it was suggested that treatment was most effective in babies born 1-7 days after administration11. This belief that steroids lasted only 7 days caused the trend of weekly repeat ACS for women not delivering within 7-10 days of receiving it, causing prolonged exposure of babies to corticosteroids. This routine began when there was almost no data from randomised controlled trials (RCT’s) to confirm that the benefits outweighed the risks. EURAIL (Europe against the immature lung) conducted a survey10 which showed a high rate of prescribing of repeated courses. One study showed that more than 50% of perinatologists were willing to give 6 or more courses of ACS12. Furthermore, in 1999 a survey in the UK revealed that of the 75% obstetric units that responded, 98% prescribed repeated courses13.
Recently, concerns have been raised about the unnecessary treatment of many patients who did not deliver prematurely. In addition, a worrying amount of evidence regarding the potential harm of ACS began to accumulate, raising concerns about adverse effects of exposure to corticosteroids, which has led to a decline in use of multiple doses.
Findings from animal studies
Some studies examining the impact of repeat steroids in rabbits14, sheep15 and monkeys16 showed decreased birth weight, brain weight and liver weight. For example, it was shown that repeat ACS treatment has noticeable effects on optic nerve myelination of sheep17. Repeat steroids also inhibited myelination in the corpus callosum, and the effect stayed until term. This finding did not recover by adulthood. However the question is whether impairment of brain development impairs later neurologic function. Long term effects of ACS on brain development and growth are unclear however one study18 showed that adult sheep exposed as foetuses to repeat ACS “showed no differences in growth parameters from control animals”.
Findings from human studies
In the late 1990’s French et al19 found an increase in the rate of growth restriction in foetuses exposed to multiple courses (33%) versus single courses (15%) ACS. Also, an Australian non­randomised cohort study of 477 neonates born before 33 weeks' gestation showed growth restriction as high as 9%20. Retrospective observational studies showed different effects on mother and infant. Concerns about adverse effects, especially long term effects on growth and development led to cautious obstetric use.
National Institutes of Health (NIH) Consensus Conferences
The NIH held a consensus conference in 1994 that reviewed all evidence on the safety of ACS21. The panel used results from a meta-analysis of 15 RCT’s, concluding that ACS use significantly reduces neonatal mortality and RDS with little risk to the infant. They recommended ACS administration “whenever the birth of an infant between 24-34 weeks gestation is likely and the mother is likely to deliver within 7 days”. Subsequent to this, the use of antenatal corticosteroids increased dramatically. Within 3 years of these recommendations, 70-90% of women who delivered babies under 34 weeks gestation had received at least 1 course of ACS22.
As more studies reported complications, the NIH Consensus panel reconvened in 2000 and concluded that these studies of repeat ACS are indicative of possible benefits, especially in reducing RDS, however due to design weaknesses caution must be used23. Cohort studies cannot be relied upon for changing current recommendations, therefore recommendations remained as previously stated and use of multiple courses was warned against (apart from in research trials). Despite this, wide variations in clinical practice continue to exist. Repeat ACS may be unnecessary and even harmful, yet withholding further treatment may jeopardize infants delivering prematurely. This article reviews the literature to examine the role of multiple courses of antenatal steroids to prevent neonatal respiratory distress syndrome.


Electronic databases were searched online; OVID (Medline), PubMed (Medline), Scopus and Science Direct. The following search terms were used “respiratory distress syndrome”, “betamethasone or glucocorticoids or steroids” and “antenatal”. The bibliographies of articles were also searched. Inclusion criteria were human studies, under 33 weeks gestation, 1-4 ACS courses given as re-treatment, randomised controlled trials, free full text and the article must examine effects of repeated courses of ACS as a prevention for RDS.


Evidence of the impact of multiple courses of ACS on neonatal birth weight, head circumference, brain growth and neurodevelopmental outcome should be performed using human studies, as results from animal studies may reflect a “species-dependent timing of exposure”24.
Guinn et al, 2001
In 2001 the first major (human) RCT to evaluate the effectiveness of single versus weekly courses of ACS was published by Guinn et al25. It was conducted in 13 academic centres in the USA between February 1996 and April 2000. Pregnant women at high risk of preterm delivery between 24- 32 gestational weeks were eligible. The trial was stopped after 500 patients were enrolled due to safety concerns emerging in new literature.
No difference was observed in the primary outcome between the groups. For example, mean birth weights were 856 grams (g) and 876g in the treated and placebo groups respectively a non-statistically significant difference. The head circumferences were not significantly different either. A secondary analysis showed that infants most likely to benefit from repeat ACS were born between 24-27 weeks. It was concluded that the data suggested “a possible benefit of repeated ACS in terms of morbidity at early gestational ages and a reduction in severe RDS, accompanied by a possibly harmful but small effect on growth”.
Wapner et al, 2006
This RCT was conducted at 18 centres in 200626. Eligible women were randomized to weekly injections of ACS or placebo until delivery or until 33 weeks and six days' gestation. Number of courses were reduced to only four after the first 67 patients were enrolled, in view of safety concerns. After an interim analysis, babies in the repeated ACS group were shown to have decreased birth weight with no benefit to neonatal outcome hence the study was aborted. Altogether a total of 495 patients were enrolled out of an anticipated 2400. There were no differences between the two groups in morbidity. However surfactant administration, use of mechanical ventilation, and occurrence of pneumothorax were significantly less in the repeat ACS group but a 95g significant reduction in birth weight was also found. There were significantly more infants in the repeated ACS group with birth weights less than the 10th and 5th percentiles.
Physical and neurological examinations were carried out on 486 of the infants at 2-3 years of age. Both repeat ACS and placebo groups were similar in physical dimensions and general health measures. Six children in the repeat ACS group, and one in the placebo group had cerebral palsy. The authors concluded that weekly repetition of ACS to all women at high risk of preterm birth “cannot be justified, may be harmful, and requires treatment of many infants who receive little or no benefit”.
Crowther et al, 2006
The largest clinical trial so far was conducted in 16 Australian and 7 New Zealand hospitals and published in the Lancet27. Recruitment took six years and three months and resulted in a sample size of 982 women and 1146 babies. 42% of women received one additional dose, 22% received two additional doses and 36% received three or more additional doses. Repeated ACS treatments decreased not only rates of RDS, but duration of mechanical ventilation, the need for oxygen therapy and the need for surfactant therapy. Neonatal weight and head circumference were reduced at birth but were normal by the time of hospital discharge.
96.5% of the children were followed up at two years of age and no differences were found between the repeated ACS and placebo groups in body size, disability, lung disease or ‘general health measures’. Both groups of children scored similarly on the Child Behaviour Checklist, with the exception of attention problems- children in the repeated ACS group were “significantly more likely to need further assessment”.
Garite et al, 2009
Garite and colleagues’ RCT was conducted between May 2003 and February 2008 in 18 private and university medical centres28. Patients were randomized to receive one additional rescue course of ACS or placebo. Composite morbidity, RDS and use of surfactant in the ACS group was significantly reduced compared with the placebo group, but there was no reduction in the need for ventilator therapy. Rates of perinatal death, birth weights and head circumference were similar. No trend was found in reduced body or head growth in the ACS group.


Studies found either a small effect of ACS on foetal growth or no difference, and concluded that there may be harm in repeat ACS, recommending limiting the number of courses administered. However are their findings conclusive? All studies described good methods in allocation of patients into the groups and ensured participants and staff were blind to the study groups, which limited participant and observer bias, making results more valid. They have also attempted to limit potentially confounding variables by strictly defining the study population to a limited gestational age, and not including women who experienced premature rupture of membranes. However there are various methodological problems with these studies.
The evidence in both Guinn and Wapner’s RCT’s sounds encouraging; however, by not completing theRCT as originally planned, conclusions made about efficacy may be invalid.The study may not have been large enough toanswer the question. Because of the smaller than planned sample size, the study lacks statistical power to determine the effectof repeat courses of ACS or to detect slight differences between the groups. This renders the findings of this trial inconclusive.
Furthermore Guinn’s trial shows data from the cohort of 308 patientsfrom the interim analysis and the patientssubsequently enrolled. Clearly, there was higher morbidity in the weekly ACS group in the second cohort than the first.If the authors calculated the ‘probability of showing abenefit’ for repeated ACS at the time of ending recruitment(502 patients), a more than 75% chanceof demonstrating efficacy at 1000 patients would have been found (if the trend hadpersisted). It is true the trend could have changed in the next 500 patients, but this shows how halting RCT’sbased on beliefs of what may or may not occur may lead to unclear conclusions.
Moreover, all trials with the exception of Garites trial did not provide data comparing the baseline characteristics of women of the time to delivery subgroups. Women who deliver more than seven days after randomisa­tion may differ from the others in age, number of previous pregnancies, ges­tational age, reasons for the risk of preterm birth, as well as other factors. Any differences between subgroups may therefore be caused by differences in the subgroups and not the effectiveness of repeat courses of ACS. The likelihood of bias cannot therefore be assessed.
The trials recruited women with a gestational age of fewer than 36 weeks. Almost all babies born at term, i.e. over 37 weeks, were therefore in the subgroup of babies deliv­ered seven or more days after randomisation. Because death and RDS are rare in babies delivered at term; fewer outcomes would be seen in this subgroup, so a statistically significant differ­ence would be less likely to be found. Therefore, not finding a difference may simply be because of the lower occurence of outcomes in babies born at term. (In a 2006 review, incidence of RDS in three subgroups29is consistent with this argument- 27.5% in the
As reduction in head circumferences seen at birth are relatively small, the concern is the effects on brain growth. In studies that did suggest a damaging effect, minimal or no effects were seen until 3 or more courses of ACS were administered. Even though associations were shown in these studies, causation has not been confirmed; therefore it is difficult to interpret these findings.
Further trials addressing this question are needed, especially since the trials of Guinn et al and Wapner et al couldhave demonstrated a beneficial effect of repetitive courseswith minimal risks. Arising from this are several implications for education and practice and implications for further research.


There is evidence that courses of ACS improve pulmonary outcomes in the neonate, preventing RDS. There is evidence suggesting potential harm, and the lack of long term safety data, caution and careful patient selection is required when instituting this intervention.


1. National Centre for Health Statistics. Infant and perinatal mortality. (Vital and Health Statistics, Analytical Studies, Series 3, No. 9). Washington, DC, US Department of Health, Education and Welfare, 2004.
2. Laws PJ, Sullivan EA. Australia’s mothers and babies. Australian Institute of Health and Welfare, National Perinatal Statistics Unit (Perinatal Statistics Series no.15), 2004.
3. Avery, M.E, & Mead, J. Surface properties in relation to atelectasis and hyaline membrane disease. Amer.J.Dis.Child. 1959; 97: 517-523
4. Antenatal glucocorticoid therapy for the prevention of RDS in the premature infant. Am J Obstet Gynecol. 1977;50 (2):186-190
5. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol.1995;173:254-62
6. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515-523
7. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for the prevention of respiratory distress syndrome in premature infants. Peadiatrics. 1972;50:515-525
8. Papageorgiou AN, Desgranges MF, Masson M, Colle, E SHantz R, et al. The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study. Peadiatrics. 1979;63:73-79
9. Kikkawa, J., Kaibara, M., Motoyama, E. K., Orzalesi, M.M & Cook, C.D. Morphologic development of foetal rabbit lung and its acceleration with cortisol. Amer. J. Pathol. 1971; 64: 423-433
10. Empana JP, Anceschi MM, Szabo I, Cosmi EV, Breart G, Truffert P. Antenatal corticosteroids policies in 14 European countries:factors associated with multiple courses. The EURAIL survey. Acta Paediatr 2004; 93:1318-22
11. Howie RN, Liggins GC, Anderson ABM, Beard RW, Brudenell JM, Dunn PM. Clinical trial of antepartum betamethasonetherapy for prevention of respiratory distress in pre-term infants. Pre-term labour. 1977:281-9
12. Planer BC, Ballard RA, Ballard PL, Coburn C, Boardman A, Cnaan A, et al. Use of antenatal corticosteroids (ANCS) in USA. Am J Obstet Gynecol 1998;174:A576
13. Brocklehurst, P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK. Br J Obstet Gynaecol 1999;106:977-9
14. Tabor BL, Rider ED, Ikegami M, Jobe AH, Lewis JF. Dose effects of antenatal corticosteroids for induction of lung maturation in preterm rabbits. Am J Obstet Gynaecol 1991;164:675-81
15. Jobe AH, Wada N, Berry LM, Ikegami M, Ervin MG. Single and repetitive maternal glucocorticoid exposures reduce foetal growth in sheep. Am J Obstet Gynaecol 1998;178:880-5
16. Uno H, Lohmiller L, Thieme C, Kemnitz JW, Engle MJ, Roecker EB, et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. Dev Brain Res 1990;53:157-67
17. Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci 2001;19:415–25
18. Moss TJ, Doherty DA, Nitsos I, et al. Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol 2005;192:146–52.
19. French H, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynaecol 1999; 180:114-21
20. French N, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114­21
21. Effect of antenatal steroids for fetal maturation on perinatal outcomes. NIH Consensus Statement 1994 Feb 28-Mar 2;12(2):1-24
22. Leviton LC, Golderberg RL, Baker CS, et al. Methods to encourage the use of antenatal corticosteroid therapy for fetal maturation: a randomized controlled trial. JAMA 1999; 281:46-52
23. Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement 2000:17 (2):1-10
24. Ballard PL, Benson BJ, Brehier A: Glucocorticoid effects in the fetal lung. Am Rev Respir Dis. 1976; 115:29
25. Guinn DA, Atkinson MA, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial. JAMA 2001; 286:1581-1587
26. Wapner RJ, Sorokin Y, Thom EA, et al. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynaecol 2006;195:633-642
27. Crowther CA, Haslam RR, Hiller JE, et al. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomized controlled trial. Lancet 2006;367:1913-1919
28. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a ‘recue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009;200(248):e1-248.e9
29. 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.

Source(s) of Funding


Competing Interests



This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.


Author Comments
0 comments posted so far


What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)