Miscarriage is the commonest complication of pregnancy. One in four women will experience a pregnancy loss and about 15% of all pregnancies will end this way.
While the physical process of pregnancy loss is unpleasant it’s often the emotional trauma that is most distressing.
The grief of miscarriage can last forever
Julia Bueno, Author of The Brink of Being: An award-winning exploration of the psychological, emotional, medical, and cultural aspects of miscarriage and pregnancy loss.
Why did it happen?
The most frequently asked question after a miscarriage is why did it happen? We know that most pregnancy losses occur due to a chromosomal problem called aneuploidy. Aneuploidy is a condition in which the cells in the developing embryo have an incorrect number of chromosomes. Many miscarriages are unexplained. Testing after three pregnancy losses still doesn’t find a cause for 1 in 4 women.
- A condition when a cell has the incorrect number of chromosomes.
- Humans normally have 46 chromosomes in 23 pairs.
- An extra chromosome 21 causes Down’s syndrome.
- A missing X chromosome causes Turner’s syndrome.
- Incorrect numbers of other chromosomes are a common cause of miscarriage.
What about Progesterone?
Progesterone is a hormone vital for pregnancy and produced by the corpus luteum on the ovary after ovulation occurs each cycle to maintain the lining of the womb for implantation of an embryo. If pregnancy does not occur, progesterone levels fall resulting in a period. If an embryo implants the ovary should continue to produce progesterone to support the pregnancy until the placenta is big enough to continue making progesterone.
Progesterone is essential for pregnancy. Medications that counteract progesterone cause termination of pregnancy or induce labour.
Given progesterone’s fundamental role, doctors have tried supplementing progesterone to reduce the chance of pregnancy loss. However, until recently, the research to support this practice was limited.
Levels of Evidence?
We have all heard stories of people who have done certain things that they believe are responsible for a positive pregnancy outcome. This ranges from logical approaches such as using progesterone, to possible interventions like herbal medicine all the way to nonsense such as eating McDonalds chips after an embryo transfer.
Take this case study. A young woman with six miscarriages. She then took progesterone and had a baby but miscarried in her next pregnancy. When pregnant again she had progesterone and had a baby. Looking at this case, you would easily and logically think it was the progesterone that made the difference.
Nevertheless, to get good evidence that progesterone is beneficial, and perhaps more importantly, that it isn’t harmful we need to take a more scientific approach.
The highest quality of evidence is a randomised controlled trial (RCT). This is where a group of women are randomly allocated to either the treatment, in this case progesterone or a placebo. For a trial to provide convincing results, it needs to include enough patients and neither the patients nor researchers should know which treatment they receive until the end of the study.
Randomised Controlled Trials are expensive to carry out and rely on patients and doctors being prepared to toss a coin to decide on which treatment to use. Sadly, many previous trials of progesterone to prevent miscarriage were too small or were biased resulting in more uncertainty.
Two definitive trials
In the last few years two large high-quality trials have been completed to address these two important questions.
- Does progesterone treatment increase the rates of live births in women with unexplained recurrent miscarriage.
- Does progesterone treatment increase the rates of live births in women with vaginal bleeding in early pregnancy.
The first question was addressed by the PROMISE trial. Over 800 women took part. The results showed 65.8% of women in the progesterone group and 63.3% in the placebo group had a baby. These are similar rates in each group and not shown to be statistically different.
The second question was addressed by the PRISM trial. Over 4000 women took part. The results showed 75% in the progesterone group and 72% in the placebo group had a baby. Again, these are similar rates in each group.
On the face of it, this is disappointing as progesterone did not appear to be effective. However, the first take home message is that even with no treatment the chances of having a baby after recurrent miscarriage or bleeding in early pregnancy are high. No IVF clinic would be able to get a live birth rate of over 60%. This must be reassuring for women.
A closer look
The researchers planned further analysis of PROMISE and PRISM. Looking closer they found an interesting effect.
Overall, there was little difference between progesterone and placebo. However, if you looked at groups of women who had previous pregnancy losses the effect was greater. Why would this be the case?
Previous research shows that the more miscarriage a woman has, the more likely it is to be chromosomal normal. No matter how much progesterone you give, it cannot prevent the miscarriage of an aneuploid pregnancy. But as women with a previous miscarriage are more likely to have a chromosomally normal pregnancy, they are more likely to benefit from progesterone.
UK NICE Guidance
Based on the results of the PROMISE and PRISM trials, national guidance in the UK was changed to recommend vaginal progesterone for women with early pregnancy bleeding and a previous miscarriage.
Summary
Webinar
Sources
Coomarasamy. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages. NEJM. 2015.
Ectopic pregnancy and miscarriage: diagnosis and initial management. NICE. Updated 2021.
Authors
Matt is an NHS Consultant in Newcastle with over ten years of experience. His PhD research into subfertility and miscarriage involved developing a clinical trial and patient engagement.
