Steroids in pre-term labour: to repeat or not?

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Hans van der Slikke, MD, PhD:  “It’s April 2003 and we’re in Berlin at the Controversies in Obstetrics and Gynaecology Conference and next to me is Mary Hannah from Toronto; welcome, Mary.”

Mary Hannah, MD:  “Thank you.”

Hans van der Slikke, MD, PhD:  “You presented a poster about your steroid trial. We all know that it took many, many years after the first publication of Liggins that the steroids became normal practice. This is often seen as an example of how long it takes before evidence is turned into practice in contrast to your presentation about your paper about breeches. But at that time it became more and more practice to repeat a shot of steroids after 10 – 14 days, and now in the last years the question raised is if this is useful or maybe if it’s still useful with the modern ICU settings and if it doesn’t damage the baby too much? So I’m sure that must be one of the reasons you set up this trial.”

Mary Hannah, MD:  “The trial was actually set up when practice was much more towards repeating the courses of steroids, and it’s interesting that that all happened without much evidence. It took a while to get people to use steroids, even though there was very good evidence, but there wasn’t good evidence to repeat the courses. The data suggested that the benefits might wear off after about seven days but there had been no trials until recently of the benefits of repeating the steroids. It was common practice to do so. 

And then a number of years ago concern was expressed that this practice might a) not be beneficial and b) might be associated with risks to the baby and therefore probably should be stopped until benefits were shown to outweigh risks. 

A number of randomised control trials are underway to assess whether benefits outweigh risks of repeating courses of steroids, which just emphasises the importance of the question, that it’s being studied by a number of groups. 

Interestingly most groups are assessing the use of, or the benefits of, repeating steroids every seven days. In our ongoing trial, MACS, which is led by Kellie Murphy in Toronto, we’re assessing the benefits of repeating courses of steroids every 14 days and then only if the risk for pre-term birth is continuing. So if the risk for pre-term birth has gone away then the treatment does not continue, but if it goes away but then comes back again then the treatment starts up again. 

So we’re trying to minimise the exposure of the foetus to steroids but on the other hand assessing the use of repeating the steroids. There is no question there is potential for benefit but it’s not without potential risk.”

Hans van der Slikke, MD, PhD:  “When in your trial do you start? Which term? Which gestational age?”

Mary Hannah, MD:  “To be eligible for MACS, for this randomised control trial, women need to have received one course of antenatal steroids already and be 14 to 21 days after that. They are eligible to join the study if that’s happened and they are 25 or more weeks gestation up until 32 weeks gestation.”

Hans van der Slikke, MD, PhD:  “And does it matter what kind of tocolytics are used?”

Mary Hannah, MD:  “No we’ve left the use of other treatments up to the clinician, tocolytics, antibiotics, because the evidence is variable as to the benefits of those treatments. So we haven’t said you shouldn’t use them or you should use them. We’ve left that up to the clinicians to decide but we are recording that information so at the end of the study we’ll be able to report on which drugs were used and how often they were used.”

Hans van der Slikke, MD, PhD:  “How many centres do you have now in the United States and Canada versus the centres in Europe or the rest of the world?”

Mary Hannah, MD:  “There are about eight to 12 countries I’d say…there is a variation because I’ve been away for a few days and we have a number of centres and countries starting up, who are participating in MACS. 

Canada is obviously participating very strongly in MACS but we have a number of centres in Europe. 

I think the Canadians perhaps have enrolled more women than any other country at this moment, but Poland is actually a very strong contributing centre and other centres in Europe; Germany is contributing a fair bit, and the Netherlands as well. There are some centres in Spain and Portugal that are working on coming into the study. 

In the UK we have not had any centres participate as of yet although we anticipate a number will join us soon and that is because in the UK they were running a multi-centre trial of steroids themselves and so obviously were participating in that. That study has recently stopped recruiting, principally due to problems with funding and so we anticipate a number of centres from that study group will now join MACS and help answer the question that way. 

But there is a large trial in Australia going on at the moment, which is further along than MACS. I think they’ve recruited about 700 or 800 women and their sample size is about 900, I believe, so they should be finishing that study soon. MACS has a sample size of 1900 so we’ve still got a way to go and we’re around 450 right now. 

But I anticipate that with these trials, now the one in Australia is repeating courses every seven days, MACS every 14 days, so I think we’re in a very strong position because together we will probably be able to nail this problem and answer the question one way or another. So MACS will make its contribution by looking at the use of steroids every 14 days.”

Hans van der Slikke, MD, PhD:  “So centres are still invited to participate in your study because you need about 1400 patients more.”

Mary Hannah, MD:  “Yes, absolutely. The key component about participation in MACS is the ability to follow women and babies because we feel that a two-year follow up is very, very important that we look at neuro-developmental outcomes in these children. 

So we are currently only inviting centres that feel that they can follow over 80% of all their children. And the outcome for the baby at two years is a neuro-developmental assessment using the Bayley Scales of Infant Development, which is somewhat time intensive and is not something that every centre can easily do. So there are some caveats about participation but we have had centres join MACS that previously had not been able to do the Bayley but since joining they are now training people to do it. 

We are also talking about a longer-term follow up in MACS up to six to seven years for the children because we feel we need to know that benefits outweigh risks over the long-term. So we would be delighted if more centres would like to come to join us.”

Hans van der Slikke, MD, PhD:  “We will help you to invite the centres. I am looking forward to the result. Thank you very much.”

Mary Hannah, MD:  “Thank you.”

http://www.utoronto.ca/miru/macs/index_macs.htm?/miru/macs/macs.htm