From the 4th World Congress on Controversies in Obstetrics, Gynaecology and Infertility  

An update on tocolytics

Herman P. van Geijn, MD, PhD interviewed by Hans van der Slikke, MD, PhD

• View the interview (requires free Windows Media Player)

Hans van der Slikke, MD, PhD: “It’s April 2003, we’re in Berlin at the Controversies in Obstetrics and Gynaecology Conference, and next to me is Professor Herman van Geijn - very welcome! You are the Professor of the VU Medical Centre in Amsterdam, a university, which is well known because of its work in pre-term labour and tocolytics. You had a wonderful presentation about tocolytics this afternoon where you talked about the old and the new way to try to stop labour. Could you comment on your presentation, please?”

Herman van Geijn, MD, PhD: “I think there have been a couple of changes in the last year, where up to ten years ago, there was only one drug – or at least one type of drug – a beta-agonist, which was used by nearly all of us in obstetrics to stop labour. It was not a very elegant drug, there was a lot of side effects, particularly for the mother, but also for the foetus. But in the early 90s, there appeared a promise in another type of drug, a calcium-channel antagonist. It became attractive because you can administer it orally, it had less side effects, and a number of studies have been done, I think we did the largest randomised study and, indeed, it came out much better than the group of beta-agonist drugs.

In the meantime, there have been developments on an oxytocin antagonist, which is a drug that acts more directly upon the uterus in contrast to the beta-agonist and the calcium channel blockers, and the development was simultaneous with the studies on the calcium channel blockers, (nifedipine) and we are now in a situation where there are three major drugs being used in the world to stop pre-term contractions. One type of drug (the beta-agonists) is not very favourable anymore, although it is still used."

Hans van der Slikke, MD, PhD: “Recording, so the betamimetics, we all know they have a lot of side effects, especially in the mother, but you said as well in the foetus. What kind of side effects are there for the foetus?”

Herman van Geijn, MD, PhD: “Particularly the heart rate. The heart rate increases substantially, and if you monitor the condition of the foetus, we are fully dependent on the monitoring of the heart rate patterns, you can easily get confused.”

Hans van der Slikke, MD, PhD: “Especially because it hides threatening infection, where you see the heart rate rise?”

Herman van Geijn, MD, PhD: “There are a couple of reasons why the heart rate can rise. It can be just a compensatory reaction to a minor or moderate degree of hypoxia, that’s the only way for the foetus to improve its cardiac output and to supply sufficient oxygen to the foetus’ organs. So that’s one reason for an increase in the heart rate. Another reason is infection, either in the mother or in the uterus. Both increase the heart rate and then, of course, there are the drug effects. So you come to a point where you don’t know what is happening to the foetus anymore.”

Hans van der Slikke, MD, PhD: “So, I think we can conclude, the same as you did in your presentation, that there is no place anymore for the betamimetics?”

Herman van Geijn, MD, PhD: “I think they are too dangerous, with too many side effects. They are drugs that you should not apply anymore if you think of the interest of the mother and the foetus.”

Hans van der Slikke, MD, PhD: “But then we have the calcium blockers and you showed with Papatsonis in your study that they do have effects, they prolong pregnancy, and they have only a few side effects, not very serious in most cases. But the problem is that this drug is not licensed.”

Herman van Geijn, MD, PhD: “Yes, that’s correct, and they will not be licensed either, and the reason is the industry is not interested in it. In the meantime, there is another drug on the market that has a lot of potential, too. So I don’t think another company will start working on these calcium channel blockers. They have a certain attraction: you can use them orally, they are effective, they definitely have a better result concerning the neonatal morbidity than the beta-agonists.

The problem is it’s not licensed by the company and there has been not so much money put into it as in the other two drugs, particularly atosiban. We don’t have such extensive data: studies are less homogeneous, the inclusion criteria are different, the end points are different, strategy is different, and dosis is different. So there is a major problem now when you compare calcium channel blockers, with the oxytocin antagonists.”

Hans van der Slikke, MD, PhD: “So what kind of research would you suggest?”

Herman van Geijn, MD, PhD: “It would be ideal to compare them With strict inclusion criteria, because you can’t use nifedipine in all patients. You must stratify for the duration of the pregnancy, and you cannot do it blindly.”

Hans van der Slikke, MD, PhD: “No that is impossible because one is orally and the other one is intravenous.”

Herman van Geijn, MD, PhD: “It’s frequently commented on these studies that you didn’t do a blinded randomised trial. However, in this case you simply cannot.”

Hans van der Slikke, MD, PhD: “It’s impossible?”

Herman van Geijn, MD, PhD: “Yes, and you could only do sham IV infusions but that’s not reasonable to do, also because of the actions of the drug.”

Hans van der Slikke, MD, PhD: “So you will have a randomised study that is not blinded again?”

Herman van Geijn, MD, PhD: “Yes, that’s a disadvantage. And one medication is oral, one medication is intravenous, but still, it would be worthwhile to compare them.”

Hans van der Slikke, MD, PhD: “The only way would be that you give the patients an intravenous drug and a placebo, or a placebo and the other group then orally, as well, so it’s a double – a double-double.”

Herman van Geijn, MD, PhD: “Yeah, you could do it. I don’t know if it will pass ethical committees, but you definitely could consider it. There was no way to consider it in comparing betamimetics because they have so many side effects you would immediately know.”

Hans van der Slikke, MD, PhD: “Immediately!”

Herman van Geijn, MD, PhD: “With atosiban, the risk is less, so you could. I wonder how ethical committees will react to this if you give an IV just for a study?”

Hans van der Slikke, MD, PhD: “As long as the study is not done, what is the situation now and the knowledge that we have now?”

Herman van Geijn, MD, PhD: “If you look at licensing, that was our starting point, ritodrin was licensed for 36 to 48 hours, atosiban has its license for 36-48 hours; nifedipine is not licensed at all. After the first two days, any drug is still attractive to study further, and I think we really should focus more on maintenance therapy. I’ve never understood why you change a winning team.

If a pregnancy has a duration of 24, 25, 26 weeks, you know that the chance of survival at one year of age for the infant increases 3% per day. I don’t understand why you would stop good treatment and, in that regard, maintenance therapy either with atosiban or with nifedipine should be studied further. Particularly for maintenance therapy, nifedipine is attractive to look at because it’s oral so you need less manpower, particularly from the nurses and midwives, there’s less chance to make mistakes with intravenous infusions, you can mobilise patients easier at some point.

I think in that sense it might be interesting to do a study where you start with atosiban intravenously for 36 to 48 hours and then you switch to nifedipine, or placebo because it has to be proven that maintenance therapy is worthwhile to pursue in the future. I particularly would like to do that study.”

Hans van der Slikke, MD, PhD: “Well, we are looking forward to it. Thank you very much.”