The safety of new drugs in pre-term labour with multiple pregnancies

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Hans van der Slikke, MD, PhD: “It’s April 2003, and we’re in Berlin at the Controversies Conference. Next to me is Professor Gian Carlo di Renzo, from Perugia, Italy. Very welcome, Gian Carlo, back again in our studio! Today you did a presentation about pre-term labour in multiple pregnancies and the new drugs you use. Tell me about the set-up of your study.”

Gian Carlo Di Renzo, MD, PhD: “First of all, I would like to point out that pre-term labour not only is obviously more frequent in multiple pregnancies but should be considered in a time-frame of gestation as quite different from the pre-term labour in singletons. That is to say that if I consider a twin pregnancy physiologically at term at around 37 weeks, I think I consider it pre-term when it’s before 35, which is a little bit different than in a singleton; this is also true for triplets. 

On average, if we look at data coming from all over the world, we have three times more incidence of true pre-term labour in multiple pregnancies compared to singletons. Therefore it is a very important issue considering that 50% of mortality for multiple pregnancies also came from delivery before 30 weeks, related to the very pre-term babies. So it is a relevant issue, it’s a clinically important issue, it’s a frequent issue, since we are dealing more and more every day with these multiple pregnancies: because of ageing of the woman, because of reproductive technologies, and so on. 

One important issue is: what to do? You know that prevention or prediction is still very debated and we are at a very early stage of our capabilities to understand when a patient is at high risk – what can we do? Even though we identify the patient as high risk, now it seems that only progesterone, a very high dosage, can help. 

However, this has been proven in singletons, not for multiples. But, in any case, there is a widespread philosophy to act with a tocolytic drug to give something that inhibits uterine contractions, and this is the second important issue in my presentation. Which is the best drug at the moment? What do we have to do? 

You know that so far many tocolytic drugs have been used like, you know, the betamimetics, the calcium antagonists, the magnesium sulphate, and I have just mentioned prostaglandin inhibitors and glyceril trinitrate. However, all these glyceril drugs are targeting several systems in the body of a mother and also in the foetus, so they are not targeting just the uterus.”

Hans van der Slikke, MD, PhD: “No, and with the ritodrin, which is the exponent with the most side effects in general?” 

Gian Carlo Di Renzo, MD, PhD: “Yes, generally ritodrine (a betamimetic drug) has the most side effects of the betamimetics drugs and especially you have to consider that in multiple pregnancies, we know they are even worse for two reasons: First, because the cardiac output in multiples is doubled, at least compared with the singleton, and it has been shown that if you administer a betamimetic drug to a multiple pregnant woman, you triplicate your cardiac output, which means you put the patient in a very stressful and risky situation. Secondly, that all the metabolic effects of betamimetics are likely to give a lower potassium level, increased glycaemia, and so on from the background, which is already altered because of the multiple pregnancy metabolism, so it’s a further enhancement of this metabolism alteration and this may be further dangerous, especially the effects of hyperglycaemia and hypokalemia.”

Hans van der Slikke, MD, PhD: “This is what may put the woman really at risk?" 

Gian Carlo Di Renzo, MD, PhD: “Yes, and in fact there is, at least from the overall reporting in the literature, case reports of pulmonary oedema associated with betamimetics; in at least one-fourth of the statistics this is connected with multiple pregnancy. That is to say that any one out of every ten women with a multiple pregnancy risks pulmonary oedema if you use betamimetics. So I think that we have to make it clear to ourselves to ban these tocolytic agents, especially in the cases of high-risk pregnancies. 

So what to use? All the other have other controversial side effects and now in our arena, in our armamentarium, we have a new drug, which is Atosiban, which is an oxytocin-antagonist which interacts with the receptor of oxytocin, blocking the receptor, and having an effect only at 99% on the uterus because if there is another effect on the other oxytocin receptor in the body, this is negligible. The drug is therefore safe and shown not to have any side effects. 

This drug is coming in as the first line treatment for this kind of patient, and can be used safely not only for the 48 hours (as being shown by several randomised trials now, which has been also considered in the Cochrane database) but also from our own and the Vienna group which have experienced longer treatment periods with Atosiban, up to 20 days even, and safely without changes in the metabolism of the mother and bringing very good results, especially in multiple pregnancies. 

I’ll just report one anecdotal case of triplets: we admitted the patient at 22 weeks with one baby already delivered; the other two were stopped in utero. We are familiar with delaying delivery in this kind of pregnancy. We use Atosiban bolus to stop contractions, and we were able to continue the pregnancy for another couple of weeks until it was unavoidable to deliver the other two babies. Then one baby died unfortunately, but the other is safe, is growing well, and has no neurological problems. So, at least from 22 week triplets, there could have been a simple abortion, we now have a pre-term baby, but he is safe and normal. 

Hans van der Slikke, MD, PhD: “So concluding, you stressed that especially in multiple pregnancies, the advantage of a new drug, like Atosiban, is much bigger than in singletons?”

Gian Carlo Di Renzo, MD, PhD: “Yes, I think there is no space for other drugs, either in the case of premature rupture of the membranes where you may use antibiotics or a short-term corticosteroids because delivery may be imminent; or in a multiple pregnancy, in high-risk pregnancies in many cases, I think that Atosiban should be the first line. 

Now for singletons, I still consider it the most indicated drug, but obviously this should be compared to the fact that we have to understand better how many patients we treat, because you know that it is reported everywhere that 50% of patients who come “feeling” contractions don't go into labour, so we have to ameliorate our diagnostic tools, for instance, more usage of fibronectin, more usage of cervical ultrasonography and other, you know, biochemical, vaginal for instance microbiological evaluation and so on, in order to be able to target the problem, otherwise we use a powerful drug in cases in which there is no sense to use it.”

Hans van der Slikke, MD, PhD: “Yes, otherwise diagnostics like proteomics now are fairly good to see if there’s an infection or not.”

Gian Carlo Di Renzo, MD, PhD: “Yes, for instance. Or even to perform a vaginal pH, and then go farther. If this is high, then we may find out the micro-organism which is involved and treat it.”

Hans van der Slikke, MD, PhD: “Okay. Thank you very much.”

Gian Carlo Di Renzo, MD, PhD: “My pleasure.”