"Every effort should be made to treat women with a course of steroids prior to pre-term delivery. (A course consists of betamethasone 24mg or dexamethasone 24mg in divided doses)"

This is the only obstetric standard given by CESDI for the assessment of cases in Project 27/28. It is based on RCOG (Royal College of Obstetricians and Gynaecologists) guidelines (1) and conclusions made by the Cochrane database (2) However it does not answer two important questions:

• Should we be giving only one course of steroids to at risk mothers?
• Should we be using betamethasone or dexamethasone?

Steroids reduce the incidence of RDS (Respiratory Distress Syndrome) by up to 50%    (2). This was first reported on by Liggins from Auckland back in 1969 (3). He was attempting to prevent premature labour in sheep by interrupting the hypothalamic- pituitary axis and found this resulted in underdevelopment of the lung tissue of the lambs. This effect was then corrected by providing exogenous steroids. His subsequent RCT in 1972 showed that a course of betamethasone given to 20 mothers at risk of premature labour prevented, on average, 1 NND (Neonatal Death) from RDS (4). These results are dramatic but were published when neonatal services were not at the standard they are today. A number of RCTs followed backing this evidence and yet it was not until nearly 20 years later that the RCOG published a guideline advocating its use in the UK. This delay in interpreting the evidence and putting it into practice was one of the main catalysts for the development of the Cochrane database.

Liggin's original work was based on 1 course of betamethasone (24mg over 24 hours). He showed that the maximum effectiveness of the steroids was seen between 24 hours and 7 days after administration. A later meta- analysis of 12 RCTs in 1995 (5) agreed with this:

Around 20% of threatened premature labourers deliver within 24 hours but we are left with 50% who remain undelivered after 7 days (6). It has become common practice for obstetricians to give repeated weekly doses to those still felt at risk of premature delivery despite the lack of evidence supporting this. A survey of Australian obstetricians showed that 85% were happy to give repeated courses of steroids(7), as are >90% of American Obstetricians (8) and around 97% of those in the UK       (9).

What has not been proven is if multiple courses are detrimental. There are a number of animal studies showing a significant decrease in birthweight with recurrent courses of steroids ((10,11,12,13). To date, there are no completed randomly controlled trials in humans, only retrospective or observational. Of the recent studies in the literature (14,15,16,17,18,19,20), two-thirds show no additional benefit in multiple courses of steroids on the incidence of RDS whilst half note a decrease in birthweight/head circumference(14,17,19). (Only one records an increase in birthweight (20).) The follow-up on these trials is short however. Only one looked at the weight of these babies at 3 years where there was no significant difference in weight (17). So is this initial disparity in weight important? The only point that all these trials agree on is the need for a large randomised controlled trial on weekly corticosteroids before a final conclusion can be made.

There are only 2 known RCTs in progress. The preliminary report of the American study suggests that weekly doses of steroids do not reduce neonatal morbidity whilst birth weight appears to be significantly reduced, allowing for gestational age. This study is relatively small - they are aiming to recruit 500 women in total
(21).

Here in the UK, the Oxford team, led by Peter Brocklehurst, have started recruiting for the pilot TEAMS trial (Trial of the Effects of Antenatal Multiple courses of Steroids versus a single course) (9). Here in the West Midlands, only 4 out of 20 units have joined TEAMS so far, although none have recruited as yet.

The second question that needs addressing is whether we should be using betamethasone or dexamethasone. Many of the published trials use betamethasone so it may be that we are biased because we have more information about this drug.

Physiologically, we know that:

• Dexamethasone is metabolised quicker than betamethasone and therefore in the circulation for less time (22)
• Betamethasone has a higher affinity for glucocorticoid receptors (22)
• A significant decrease in neonatal mortality has been shown for betamethasone rather than dexamethasone (5,23)
  
• Both produce a transient decrease in fetal heart variability, which is more significant with betamethasone. This returns to pre-treatment values within 2-7 days (24,25)
  
• Betamethasone is more potent in accelerating lung maturity in the fetal mouse (26)
  
• Betamethasone shows enhancement of memory in mouse studies, when compared to dexamethasone (27)
  
• An observational study comparing betamethasone, dexamethasone and a no-treatment group (in the gestational age group 24-31/40) showed the incidence of cVPL (cystic periventricular leukomalacia) to be 4.4% v 11% v 8.4% accordingly. This is important because of its link with cerebral palsy. (28)

The only structural difference between the 2 steroids is on the configuration of the methyl group on position 16 (a fluoride substitution) although it has been questioned whether it is the sulfiting agent in dexamethasone that accounts for its lower efficacy (28).

A meta-analysis from the Cochrane database (5) looks at the efficacy of the 2 steroids on RDS and mortality:

The effect of both drugs on RDS is similar with the reduction seen in mortality significant only for betamethasone. However this data is based on 10 trials for betamethasone and only 4 for dexamethasone.
The suggestion is betamethasone is the more efficacious.

One of the questions raised at the forum on antenatal steroids was about the cost implications for Trusts on which steroid they use. The difference is minimal: a course of dexamethasone costs £1.63 versus £2.01 for betamethasone. An audit of this region shows that only 10% of our units are using betamethasone as opposed to dexamethasone. The other cost implication would be if we only give one course of steroids rather than multiple courses.

In summary, the evidence suggests there is no benefit in giving multiple courses of steroids but that we await the results of the TEAMS trial before we are able to make a final conclusion. On the question of which steroid we should be using, the benefits of betamethasone appear to outweigh those of dexamethasone. Surprisingly, most of our units are using the latter.

UPDATE: At its June 2001 meeting, the regional Maternal-Fetal-Medicine Group endorsed the recommendation that a single course of Betamethasone (2 doses of 12 mg, 12 hours apart) be given in pregnancies between 24 and 34 weeks with suspected or threatened preterm labour. The group also recommended that a single course of Betamethasone only should be given, unless the unit was a participant in the TEAMs randomised trial. These recommendations were circulated by WMPI to all regional Clinical Directors and Heads of Midwifery on 13.7.2001.

UPDATE 2: In July 2001 the National Institutes of Heath Consensus Development Panel published the findings from their August 2000 conference on repeat courses of antenatal corticosteroids (29). This multidisciplinary expert panel concluded that there was insufficient evidence to support the use of repeat or rescue doses of corticosteroids in clinical practice and that single courses only should be given except in the context of clinical trials.

REFERENCES:

1. RCOG Guideline No7 1996. Antenatal corticosteroids to prevent respiratory distress syndrome
2. Crowley P. Corticosteroids prior to preterm delivery. The Cochrane Library, Issue 2. Oxford: Update software;1998, Abstract
3. Liggins GC. Premature delivery of fetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515-23
4. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972:50(4);515-25, Abstract
5. Crowley P. Antenatal corticosteroid therapy: A meta-analysis of the randomised trials, 1972-1994. Am J Obstet Gynecol 1995:173(1);322-35, Abstract
6. Brocklehurst P. TEAMS protocol: Trial of the Effects of Antenatal Multiple courses of Steroids versus a single course. June 1998
7. Quinlivan JA. Use of corticosteroids by Australian Obstetricians - A survey of clinical practice. Aust NZ Obstet Gynaecol 1998;38(1):1-7, Abstract
8. Planer BC. Use of antenatal corticosteroids in USA (ABST 576). Am J Obstet Gynecol 1996;174(1 Pt2):467
9. Brocklehurst P. Are we prescribing Multiple courses of antenatal corticosteroids? A survey of practice in the UK.Br J Obstet Gynaecol 1999;106:977-9, Abstract
10. Jobe AH. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep. Am J Obstet Gynecol 1998;178:880-5, Abstract
11. Johnson JWC. Long-term effects of betamethasone on fetal development. Am J Obstet Gynecol 1981;141:1053-61, Abstract
12. Dunlop SA. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med 1997;6(6):309-13, Abstract
13. Ikegmi M. Repetitive prenatal glucocrticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med 1997;156:178-84, Abstract
14. Banks BA. Multiple courses of antenatal corticosteroids and outcome of premature neonates. Am J Obstet Gynaecol 1999;181:709-17, Abstract
15. Elimian A. Effectiveness of Multidose Antenatal Steroids. Obstet Gynecol 2000;95:34-6, Abstract
16. Vermillion ST. Neonatal sepsis and death after multiple courses of antenatal betamethasone therapy. Am J Obstet Gynecol 2000;183(4):810-4, Abstract
17. French NP. Repeated antenatal corticosteroids: Size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114-21, Abstract
18. Smith LM. Effects of single and multiple courses of antenatal glucocorticoids in preterm newborns less than 30 weeks' gestation. J Matern Fetal Med 2000;9:131-5, Abstract
19. Abbasi S. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome. Am J Obstet Gynecol 2000;182:1243-9, Abstract
20. Thorp JA. The effect of multidose antenatal betamethasone on maternal and infant outcomes. Am J Obstet Gynecol 2001;184:196-202, Abstract
21. Guinn DA. Multicenter randomised trial of single versus weekly courses of antenatal corticosteroids (ACS): interim analysis. Am J Obstet Gynecol 2000;182(1 pt2):S12, Abstract
22. Henson G.Antenatal corticosteroids and heart rate variability. Br J Obstet Gynaecol 1997:104;1219-20, Abstract
23. Ballard PL. Scientific basis and therapeutic regimes for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173:154-62, Abstract
24. Magee LA. A randomised controlled comparison of betamethasone with dexamethasone: effects on the antenatal fetal heart rate. Br J Obstet Gynaecol 1997:104;1233-8, Abstract
25. Multon O. Effect of antenatal betamethasone and dexamethasone administration on fetal heart variability in growth- retarded fetuses. Fetal Diagn Ther 1997;12:170-7, Abstract
26. Christensen HD. A placebo-controlled, blinded comparison between betamethasone and dexamethasone to enhance lung maturation in the fetal mouse. J Soc Gynecol Invest 1997;4:130-4, Abstract
27. Rayburn WF. A placebo-controlled comparison between betamethasone and dexamethasone for fetal maturation: Differences in neurobehavioral development of mice offspring. Am J Obstet Gynaecol 1997;176(4):842-51, Abstract
28. Baud O. Antenatal Glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. B Engl J Med 1999;341:1190-6, Abstract
29. National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: National Institutes of Health Consensus Development Conference Statement. Obstet Gynaecol 2001 Jul;98(1): 144-50, Abstract