The PROMISE trial: a clear result

Progesterone supplements in the first trimester of pregnancy do NOT improve outcomes in women with a history of unexplained recurrent miscarriages.

Five years after it began, the results of the PROMISE (progesterone in recurrent miscarriage) trial have now been published. (1)

They are clear, they are very important – and they are bound to be disappointing to many women and couples and to those who care for them. We had all hoped that the trial would show that progesterone is an effective treatment for those considering pregnancy after previous losses, but sadly we now know it is not.

The study of 826 women with previously unexplained recurrent miscarriage showed that those who received progesterone treatment in early pregnancy were no less likely to miscarry than those who received a placebo (or dummy treatment). This was true whatever their age, ethnicity, medical history and pregnancy history.

Nearly two-thirds of the women in the trial had their baby, whether they had progesterone or the placebo.

But there is important good news here too. After more than 60 years of debate, we now know that progesterone treatment in early pregnancy isn’t the answer for women with unexplained recurrent losses. And that means that researchers can now direct their efforts to exploring and testing other treatments that really can reduce the risk.

Disappointment

These results are bound to come as a disappointment to many thousands of women and couples affected by miscarriage.

It will be especially disheartening for anyone who has had repeated miscarriages, where specialist investigations have shown no obvious cause. For them – maybe for you reading this – every pregnancy is filled with anxiety. Every miscarriage confirms their – perhaps your – worst fears. Many hoped that this research would confirm progesterone as an effective treatment that would promise an increased chance of a ‘take-home’ baby next time. Sadly, it does not.

The trial results will be disappointing to many health professionals and NHS commissioners too. Those who care for women with recurrent miscarriage want to reduce the incidence of repeated pregnancy loss and the considerable distress it causes. Some have prescribed progesterone because they hoped it might help their miscarriage patients and now, along with their patients, they are faced with evidence that no longer supports this.

And those who foot the bill for GP and hospital care cannot look forward to the prospect of inexpensive treatment that could prevent much more costly care.

Positives too

There are some positives, however.

The first is that nearly two-thirds of the women in the trial had their baby, whether they had progesterone or the placebo. So even without treatment, the chances of a healthy pregnancy after unexplained recurrent miscarriage are better than some might expect.

The trial results also showed that there were no harmful effects of progesterone treatment for women or for their babies. That is very important information for women taking progesterone for other reasons, such as fertility treatment or for those taking part in the PRISM (progesterone in threatened miscarriage) trial.

Another important finding for women who do take progesterone in early pregnancy is that there was no sign that progesterone treatment simply delayed the process of miscarriage. Amongst those who miscarried, there was no difference between the treated and untreated women in the stage at which they miscarried.

Perhaps most important is that we finally know the answer to a clinically important question that has remained unanswered since progesterone was first proposed as a treatment for recurrent miscarriage back in 1953 (2) 1953[i]. Sad and disappointing as it is, we finally know that progesterone treatment in early pregnancy isn’t the answer for women with unexplained recurrent losses.

And that means that researchers can now direct their efforts to exploring and testing other treatments that really can reduce the risk.

So what does it mean for me?

Over time, it is likely that doctors will stop prescribing progesterone to women who are pregnant after previous miscarriages, unless there are clear reasons to do so.

Some, however, might continue. They may feel that just taking something can make their patients feel more confident and hopeful and that this alone might make a difference.

If you are currently pregnant and taking progesterone to reduce the risk of another miscarriage:

The research makes it clear that progesterone isn’t harmful to you or your baby, so it’s up to you and your doctor to discuss whether to continue it or not.

If you took progesterone in the past after having repeated miscarriages and then had a healthy pregnancy:

You may feel sure that it was the progesterone that made the difference and perhaps plan to take it in any future pregnancy/ies.   We can’t say for certain that it had no effect in your case – although the evidence suggests it is unlikely – and we wish you well whatever you decide.

And if I don’t have progesterone treatment next time? 

Above all, we hope you can find comfort in the fact that whether they had progesterone or the placebo, nearly two thirds of the women in the trial had their much-wanted baby. That means there is still a good chance of a healthy pregnancy after unexplained recurrent miscarriage without any treatment at all (3). all[ii].

 

Looking ahead

The research goes on. The PROMISE trial created a solid network of doctors, nurses and midwives across the UK and beyond, all committed to miscarriage research. They will continue to explore and test other treatments that really can reduce the risk of miscarriage, and the Miscarriage Association will continue to support their efforts in whatever way we can.


A closer look at PROMISE: what, where and who.

What

 PROMISE was a randomised, double-blind, placebo-controlled trial – the gold standard for clinical trials:

Randomised: The women who took part were given either the treatment drug (progesterone) or a placebo – a dummy drug that has no active ingredients. A computer made the selection so it was completely random.

Double-blind: The women in the study weren’t told whether they were taking the progesterone or the placebo – and neither were their doctors and midwives. So both the participants and healthcare teams were blinded to this information, to prevent any biases creeping in, while a completely separate group kept a record of who received what.

Placebo-controlled: Around half the women in the study had the active medicine and half (the controlshad the placebo, both in the form of vaginal pessaries, until 12 weeks of pregnancy.  The pessaries and packaging looked exactly the same to them and their healthcare teams.

Where

The trial was conducted in 36 hospital sites in the UK and nine in the Netherlands.

Who

Women could enrol in the study if they were 18-39 years old, and actively trying to conceive naturally after being diagnosed with unexplained recurrent first trimester miscarriage. They were also excluded from the study if they did not conceive within 12 months of being enrolled.

This is how the numbers look:

  • 1,568 eligible women were signed up to take part in the trial. Of these
  • 732 did not start the trial at all for a number of reasons (515 because they did not conceive within 12 months) and another ten either started and then stopped or were lost to follow-up. That left:
  • 826 women who completed the trial and were followed all the way through. Of these:
  • 398 women were in the treatment group and 428 were in the placebo group.
  • Their average age was 33.

And crucially, the live birth rate was

  • 65.8% (262/398) in the treatment group and 63.3% (271/428) in the placebo group.

That 2.5% is an extremely tiny difference and is not statistically significant – meaning that the difference is due to chance.

 

(1) Coomarasamy A et al. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.  N Eng J Med 2015 Nov 26;373(22):2141-8. DOI: 10.1056/NEJMoa1504927.  Link.

(2) Progesterone Inplantation in Habitual Abortion. Br Med J 1953

(3)  The chance of having a healthy pregnancy after unexplained recurrent miscarriage will depend on the mother’s age and the number of previous miscarriages.


A personal view

One of the members of our support forum took part in the PROMISE trial.

“I did the Promise trial a few years ago.  Unfortunately for me it didn’t work. However, my first 5 miscarriages were all at 5 1/2 weeks and I went to 6.5 weeks this time. I don’t know what I took – I could have had the placebo. I can’t find out until the whole trial ends, so that will be interesting.

“Although it didn’t work for me, I don’t regret doing it at all and would do it again (except you can’t take the trial more than once), As I see it, it can’t hurt and as far as my trial went, yes it didn’t help me, but if it has helped any women in the future going through what all we are, then it was well worth it.”